Alberto Enrico Maraolo

In 2019, bacterial antimicrobial resistance was associated with 4

Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen and a leading cause of severe healthcare-associated infections, particularly ventilator-associated pneumonia (VAP) and bloodstream infections (BSIs) in critically ill patients. Its remarkable capacity for both intrinsic and acquired resistance leads to complex phenotypic profiles, culminating in difficult-to-treat resistant P. aeruginosa (DTR-PA). Managing DTR-PA presents a daunting clinical challenge characterised by a narrow therapeutic armamentarium, treatment delays, and high attributable mortality. To bridge the gap between complex molecular microbiology and bedside decision-making, this narrative review employs a pragmatic, clinical vignette-based approach. Through six representative fictional scenarios of pneumonia and BSI, we systematically dissect the underlying mechanisms of resistance and their direct therapeutic implications. The vignettes explore combinations of intrinsic adaptations—such as Pseudomonas-derived cephalosporinase (PDC/AmpC) hyperexpression, OprD porin loss, and efflux pump upregulation—as well as the acquisition of serine- (e.g., GES) and metallo-β-lactamases (e.g., VIM, NDM, IMP). Grounded in the updated 2026 Infectious Diseases Society of America (IDSA) guidelines, we evaluate the optimal deployment of newer β-lactam/β-lactamase inhibitor combinations. We highlight the specific preference for ceftolozane–tazobactam in pneumonia, the roles of ceftazidime–avibactam and imipenem–relebactam, and the critical use of cefiderocol for metallo-β-lactamase producers and highly resistant phenotypes. Furthermore, the review addresses pressing clinical controversies: the superiority of targeted monotherapy over historical, toxic combination regimens; the risks of unconditionally applying “shorter-is-better” duration paradigms to DTR-PA; and the alarming frequency of treatment-emergent cross-resistance among novel agents. We also clarify common clinical misconceptions, such as the limited utility of meropenem–vaborbactam and aztreonam–avibactam against specific pseudomonal mechanisms. Ultimately, effective DTR-PA management precludes class-based empirical assumptions. By providing a phenotype-driven bedside aide-mémoire, this review reinforces that rapid recognition, direct agent-specific antimicrobial susceptibility testing (AST), pharmacokinetic/pharmacodynamic (PK/PD)-optimised dosing, and prompt source control remain the absolute cornerstones of survival for patients afflicted by these formidable infections.

Purpose: Campylobacter spp. are a common cause of acute enteric infections. In immunocompromised or elderly patients, they can lead to extraintestinal infections, including bacteremia. The clinical significance of Campylobacter bacteremia is not fully understood. Methods: We conducted a systematic review and meta-analysis on Campylobacter spp. bacteremia, including studies published up to June 2024. Results: Twenty-five retrospective observational studies, published between 1978 and 2024, were included. The studies involved a total of 2480 patients, with a mean age range across studies from 1 to 70 years; 62.45% were male. The pooled prevalence of Campylobacter species was: C. jejuni 60% [95% CI 0.45–0.73], C. coli 8% [95% CI 0.04–0.13], C. fetus 7% [95% CI 0.03–0.15], and other species 9% [95% CI 0.04–0.16]. Mortality was the primary outcome in 22 studies, with a pooled case-fatality risk of 5% [95% CI 0.03–0.09]. Univariate meta-regression showed higher mortality associated with C. fetus (β = 3.217, [95% CI 0.632–5.802], p = 0.017), immunocompromised status (β = 2.749, [95% CI 0.316–5.184], p = 0.029), and chronic liver disease (β = 5.072, [95% CI 0.424–9.720], p = 0.034). Regarding complications, secondary localizations (e.g., endovascular infections) showed a pooled prevalence of 9% [95% CI: 0.04–0.18]; relapses, 3% [95% CI 0.02–0.04]; endocarditis, 2% [95% CI 0.01–0.03]; and persistent bacteremia, 1% [95% CI 0.001–0.27]. Conclusion: Campylobacter spp. bacteremia shows a considerable risk of mortality and complications.

Bloodstream infections (BSIs) by methicillin-susceptible Staphylococcus aureus (MSSA) are a significant cause of morbidity and mortality, traditionally treated with antistaphylococcal penicillins (ASPs) or cefazolin. Ceftriaxone has emerged as an alternative due to its once-daily dosing regimen and favourable safety profile; however, its efficacy compared to the standard of care (SoC) remains controversial. This evidence synthesis aimed to assess the role of ceftriaxone in treating MSSA-BSIs. A systematic literature search was conducted in PubMed, Embase, and Scopus up to December 31, 2025 (PROSPERO protocol CRD42024595748). Studies comparing ceftriaxone to ASPs or cefazolin for MSSA-BSIs were included. Primary outcomes were 30-day and 90-day all-cause mortality . Pooled effect sizes with their 95% confidence intervals (CIs), were calculated using random-effects models, odds ratios (ORs) and mean differences (MDs) according to the type of outcome. Eleven studies totalling 2,568 patients were included. Ceftriaxone was associated with significantly increased 30-day mortality (OR 3.33; 95% CI: 2.17-5.10), although differences at 90 days were not significant (OR 1.71; 95% CI: 0.75-3.90). No significant differences were noted for clinical success (OR 0.49; 95% CI: 0.19-1.26), microbiological clearance (OR 1.66; 95% CI: 0.73-3.82). Adverse event rates were similar between groups. Given the availability of various alternatives and the consistent short-term mortality signal observed, routine use of ceftriaxone for MSSA-BSIs, especially as initial therapy, is not supported by current evidence. Only novel findings from randomized studies may change the place in therapy of the drug in this context.

Purpose: To evaluate the causal effect of ceftazidime/avibactam (C/A) combination therapy versus monotherapy on mortality and clinical success in patients with KPC-producing Klebsiella pneumoniae (KPC-Kp) infections in intensive care unit. Methods: This multi-centre, retrospective observational study (2021–2023) included adults with KPC-Kp bloodstream infections or pneumonia treated with C/A-based regimens. We employed a counterfactual framework using inverse probability of treatment weighting (IPTW) to estimate the average treatment effect on 30-day mortality. Clinical success was further assessed using Desirability of Outcome Ranking (DOOR) analysis and partial credit scoring based on patient-perspective scenarios. Results: Among 123 included patients, 77 (62.6%) received monotherapy and 46 (37.4%) received combination therapy. The combination group presented with significantly higher baseline severity, including higher APACHE II scores and rates of septic shock. In the IPTW-adjusted analysis, 30-day survival was 73.8% (95% CI: 56–92%) with combination therapy compared with 60.8% (95% CI: 46.8–77%) with monotherapy. The survival probability ratio was 1.21 (95% CI: 0.80–1.45), indicating no statistically significant survival benefit. The DOOR analysis showed a 54.7% (95% CI: 48.9%–60.4%) probability of a more favourable outcome with combination therapy, which was not statistically significant. Mean partial credit scores did not differ significantly across scenarios prioritizing survival or adverse event avoidance. Conclusions: In this cohort, C/A-based combination therapy did not provide a significant survival advantage or an improved clinical desirability ranking compared with monotherapy, after adjusting for confounding factors.

Background: Enterococcus faecium bloodstream infections (EF-BSI) cause significant morbidity and mortality in solid organ transplant (SOT) recipients, with the role of vancomycin resistance (VR) remaining controversial as an independent driver. Methods: This was a retrospective cohort study including SOT recipients with EF-BSI at our institution from 2019 to 2023. We used Cox proportional hazards regression to identify predictors of 30-day all-cause mortality. A time-dependent covariate was used to model the effects of receiving targeted, effective antibiotic therapy. Results: A total of 79 patients were included (26.6%, with VR). The overall 30-day mortality was 12.7% (10/79). In univariable analysis, septic shock (Hazard Ratio, HR: 17.1, 95% CI: 3.64–80.8, p < 0.001), the need for Continuous Venovenous Hemofiltration (HR: 6.40, 95% CI: 1.85–22.1, p = 0.003), and a Pitt Bacteremia Score ≥ 2 (HR: 5.17, 95%CI: 1.10–24.3, p = 0.038) were associated with increased mortality, while source control was protective (HR: 0.20, 95% CI: 0.05–0.76, p = 0.018). In the final multivariable model, only septic shock remained an independent predictor of 30-day mortality (HR: 11.4, 95% CI: 1.63–79.5, p = 0.014). VR was not significantly associated with mortality, though the confidence interval was wide and included clinically meaningful effects (HR: 2.07, 95% CI: 0.40–10.6, p = 0.4). Conclusions: In SOT recipients with EF-BSI, 30-day mortality is overwhelmingly driven by the host’s physiological response, manifested as septic shock, rather than the VR profile of the pathogen. The early recognition of severe sepsis/septic shock and the aggressive implementation of supportive care and source control measures in this setting are crucial.

Background: Difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA) infections are associated with high morbidity and mortality, but data on prognostic factors remain limited. Given the limited real-world data on outcomes of DTR-PA infections, we aimed to identify clinical predictors of mortality and response to therapy in this setting. Methods: We conducted a single-center retrospective cohort study of 51 patients with DTR-PA infections. The primary endpoint was 30-day all-cause mortality; secondary endpoints were clinical and microbiological cure at end of therapy. An exploratory analysis evaluated 30-day infection-related mortality. Logistic regression models (univariable, multivariable and Firth bias-reduced) were used to identify independent predictors. Results: Median age was 64 years (IQR 22); 63% were male and 71% were in the ICU at infection onset. Sepsis occurred in 80% and septic shock in 45%. Thirty-day all-cause mortality was 49% (25/51). According to multivariable analysis, septic shock was an independent predictor of mortality (aOR 5.52, 95% CI 1.04–29.27; p = 0.045) as younger age (aOR 1.06, 95% CI 1.00–1.12; p = 0.052), whereas targeted therapy with ceftazidime/avibactam or ceftolozane/tazobactam is a protective factor (aOR 0.15, 95% CI 0.02–1.17; p = 0.070) did not reach significance in the final model. Clinical cure occurred in 33% (17/51) and was negatively associated with device burden and bloodstream infection, whereas microbiological cure (45%, 23/51) was more likely with targeted therapy and absence of sepsis. The exploratory analysis of infection-related mortality (35%) showed similar predictors. Conclusions: DTR-PA infections are associated with high mortality. Septic shock and older age predict death, while the use of novel β-lactam/β-lactamase inhibitors is associated with improved outcomes. Early recognition of severe illness and timely administration of active therapy may improve survival in these infections.

The proliferation of multidrug-resistant (MDR) ESKAPE pathogens—Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.—constitutes a critical global health crisis, rendering conventional antibiotics increasingly ineffective. This comprehensive review evaluates the re-emerging potential of bacteriophage therapy as a personalized treatment for infections caused by these organisms. Phages, being viruses that specifically infect and lyse bacteria, offer significant advantages, including high specificity that spares host microbiota, self-replication at the infection site, and potent activity against biofilms. This paper synthesizes current preclinical and clinical evidence, including compassionate-use cases, for phage therapy against each of the ESKAPE pathogens. While case reports and small studies demonstrate considerable success, particularly in salvage therapy for otherwise untreatable infections, significant challenges remain. These include the narrow host range of phages, the potential for bacterial resistance, unpredictable pharmacokinetic and pharmacodynamic parameters, and a complex, non-harmonized regulatory landscape. The review highlights that phage–antibiotic synergy and the use of phage cocktails are promising strategies to overcome some of these limitations. Future progress in phage therapy will depend on standardized manufacturing, robust clinical trials to establish dosing and efficacy, and the development of adaptive regulatory pathways. Phage therapy is positioned not as a replacement for antibiotics but as a vital adjunctive tool in the armamentarium against MDR infections, heralding a move towards a more personalized approach to infectious disease management.