Nosocomial pneumonia, including hospital-acquired pneumonia and ventilator-associated pneumonia, is the leading cause of death related to hospital-acquired infections among critically ill patients. A growing proportion of these cases are attributed to multi-drug-resistant (MDR-) Gram-negative bacteria (GNB). MDR-GNB pneumonia often leads to delayed appropriate treatment, prolonged hospital stays, and increased morbidity and mortality. This issue is compounded by the increased toxicity profiles of the conventional antibiotics required to treat MDR-GNB infections. In recent years, several novel antibiotics have been licensed for the treatment of GNB nosocomial pneumonia. These novel antibiotics are promising therapeutic options for treatment of nosocomial pneumonia by MDR pathogens with certain mechanisms of resistance. Still, antibiotic resistance remains an evolving global crisis, and resistance to novel antibiotics has started emerging, making their judicious use crucial to prolong their shelf-life. This article presents an up-to-date review of these novel antibiotics and their current role in the antimicrobial armamentarium. We critically present data for the pharmacokinetics/pharmacodynamics, the in vitro spectrum of antimicrobial activity and resistance, and in vivo data for their clinical and microbiological efficacy in trials. Where possible, available data are summarized specifically in patients with nosocomial pneumonia, as this cohort may exhibit ‘critical illness’ physiology that affects drug efficacy.

The isolation of Candida may be related to comorbidity, prolonged mechanical ventilation, and survival during intensive care unit (ICU) stay, especially with non-albicans Candida (NAC). To examine the frequency of Candida isolation, associated comorbidities and outcomes in the surgical ICU in Osijek University Hospital, Croatia, the data from the electronic database from May 2016 to 30 June 2023 were analyzed. In a cross-sectional study examining 15,790 microbiological samples, different strains of Candida were observed in 581 samples from 236 patients. The control group (N = 261) was 130 consecutive patients from March to May 2019 and 131 in the same months in 2020 (pre- and post-COVID-19). Comorbidities, duration of mechanical ventilation, and survival were compared. Patients with isolated Candida were more often non-elective and had significantly more heart, kidney, and liver diseases and sepsis than the control group (p < 0.001). The duration of mechanical ventilation was 9.2 [2.2–9.24], 96 [24–146], 160 [19.5–343], and 224 [73.5–510] hours in the controls, in patients with Candida albicans, in patients with NAC, and in patients with ≥2 Candida species isolated, respectively. The mortality was significantly higher (42%) in patients with isolated Candida than in the control group (19%, p < 0.001). In a multivariate analysis adjusted for patients’ age, the Simplified Acute Physiology Score II, days of ICU, and type of admission, only sepsis on admission was an independent predictor of mortality (odds ratio = 2.27).

Background. Ventilator-associated tracheobronchitis (VAT) and pneumonia (VAP) are the most frequent nosocomial infections in the critical care setting and are associated with increased morbidity. At the same time, VAP is also associated with attributable mortality, especially when caused by difficult-to-treat (DTR) Gram-negative bacteria (GNB) that have limited treatment options. Studies have assessed the impact of nebulized aminoglycosides or colistin to improve VAT and VAP outcomes or as an adjunct to intravenous antimicrobial treatment or as a preventive approach. Objective. This overview aimed to assess systematic reviews that examine the efficacy and safety of antimicrobial nebulization for preventing and treating ventilator-associated infections in the critically ill. Methods. Systematic reviews, meta-analyses, and original randomized controlled trials and prospective observational studies were included. Searches were conducted in MEDLINE (via PubMed), the Cochrane, Epistemonikos, and PROSPERO. The methodological quality assessment was performed using standardized tools. Results. Regarding VAP treatment, the included systematic reviews presented critically low quality. The clinical response effect size to amikacin and colistin nebulization were RR 1.23 (95% CI 1.13–1.34), I2 = 47% and OR 1.39 (0.87–2.20), I2 = 56%. The main safety concern was bronchospasm with RR 2.55 (1.40–4.66), I2 = 0% and OR 5.19 (1.05–25.52), I2 = 0%. The certainty of evidence was usually very low. For VAT treatment, limited evidence showed a better clinical response and less emergence of resistant bacteria. Regarding VAP prevention, data are limited to two trials; however, only the larger one presented a low risk of bias and resulted in a reduced VAP rate. Conclusions. Delivery via nebulization might be considered in addition to IV antimicrobial treatment of GNB ventilator-associated infections. The available evidence is weak, and more studies focused on infections due to DTR-GNBs should be prioritized.

Objectives: Vancomycin is crucial for treating severe Gram-positive infections, but its narrow therapeutic index complicates dosing. Trough monitoring may inadequately reflect exposure, while AUC-guided dosing, although recommended, is often impractical. Alternative metrics such as the time in therapeutic range (TIR) and volatility index may reflect exposure dynamics. Augmented renal clearance (ARC) further challenges vancomycin therapy in Intensive Care Unit (ICU) settings. This study evaluated trough-based exposure metrics and their associations with ICU mortality and acute kidney injury (AKI). Methods: We retrospectively analyzed 109 ICU patients with sepsis receiving vancomycin. Exposure was assessed using mean trough concentrations, TIR (proportion of troughs within predefined ranges), and the volatility index, defined as the intra-individual standard deviation divided by the mean trough concentration (SD/mean). Outcomes were ICU mortality and AKI. Associations were evaluated using multivariable regression, bootstrap resampling, and restricted cubic splines. Results: TIR _>15 was independently associated with higher mortality (adjusted OR 3.88; p = 0.0326) and AKI stage II–III (adjusted OR 5.63; p = 0.0068). Higher mean troughs correlated with AKI stage II–III, whereas higher volatility showed an inverse association (adjusted OR 0.15; p = 0.0240). ARC (4.6%) occurred exclusively in younger patients and predicted subtherapeutic exposure (TIR _<10, p = 0.0485). Conclusions: Sustained troughs >15 mg/L were associated with mortality and nephrotoxicity, while the most favorable outcomes were descriptively observed at mean trough levels of approximately 8–12 mg/L, suggesting a possible narrow exposure range that requires prospective validation. These findings highlight the limitations of trough-based monitoring alone; the trough-derived metrics should be regarded as exploratory rather than validated decision-making tools.

Ventilator-associated pneumonia (VAP) remains the most frequent ICU-acquired infection and a major driver of antimicrobial exposure. Historically, clinicians treated patients for 10–14 days or longer, particularly when multidrug-resistant organisms were suspected. Current evidence from randomized trials and meta-analyses now supports shorter-course therapy (~7 days) for most immunocompetent patients with VAP who demonstrate clinical improvement. Mortality and treatment failure are not increased when compared with longer regimes. The REGARD-VAP trial demonstrated the non-inferiority of individualized ≤7-day therapy compared with conventional longer courses. This remained true even in cohorts rich in non-fermenting Gram-negative bacilli (NF-GNB) and carbapenem-resistant organisms while markedly reducing antibiotic-related toxicity. North American and European guidelines recommend 7–8 days as the default duration, with individualized extension for slow clinical response, bacteremia, uncontrolled foci, or profound immunosuppression. Additionally, biomarker-guided discontinuation, particularly serial procalcitonin (PCT), may reduce antibiotic days when used to enrich clinical assessment. This narrative review synthesizes guideline recommendations, trial evidence, biomarker-guided stewardship, and pathogen- and patient-specific scenarios to provide a practical framework for intensivists: treat until infection is controlled and the patient is improving, usually about 1 week, and extend therapy only with clear justification.

Background: Advanced cirrhosis induces profound CD4⁺ T-cell depletion through splenic sequestration and immune dysregulation. Pneumocystis jirovecii pneumonia risk thresholds remain undefined in non-HIV immunocompromised populations, necessitating investigation in cirrhotic patients. Objectives: To investigate the potential association between peripheral CD4⁺ T-cell counts and opportunistic infections (OI)—specifically Pneumocystis jirovecii (PJ)—in hospitalized patients with liver disease, and to characterize clinical outcomes across immunological risk strata. Methods: We retrospectively analyzed 455 adults hospitalized in a single institution with hepatic disorders. CD4⁺ T-cell counts were available in 227/455 patients. Among these, 22 patients met predefined immunological risk criteria (CD4⁺ < 500/µL and/or HIV positivity) and were classified into three immunological risk clusters (IRCs): IRC-A (HIV−, CD4⁺ < 200/µL; n = 9), IRC-B (HIV+, CD4⁺ < 200/µL; n = 7), and IRC-C (HIV−, CD4⁺ 200–499/µL; n = 6). PJ PCR testing was evaluated when available. Results: Among 455 patients, in-hospital mortality was 103/455 (22.6%). Of the 22 immunologically at risk patients, 15/22 had cirrhosis. PJ PCR was performed in 8/22 patients (IRC-A: 2; IRC-B: 4; IRC-C: 2), with 3/8 positive (37.5%): IRC-A (1/2), IRC-B (1/4), IRC-C (1/2). Ct values ranged from 27.0 to 31.7. Two PJ-PCR–positive cirrhotic patients (IRC-A: n = 1; IRC-C: n = 1) survived without specific anti-PJ therapy; one HIV-positive patient (IRC-B) received trimethoprim-sulfamethoxazole and survived. In-hospital mortality was 5/9 (55.6%) in IRC-A, 2/7 (28.6%) in IRC-B, and 3/6 (50.0%) in IRC-C; none of the deaths were attributable to PJ pneumonia. Conclusions: Severe CD4⁺ T-cell depletion (<200/µL) was common among cirrhotic patients and associated with PJ detection (3/8 tested), but not with PJ-related mortality (0/3). Mortality was primarily driven by hepatic decompensation and bacterial infections. CD4⁺ assessment may improve risk stratification in cirrhosis; however, prospective, multicenter studies are warranted to validate these findings and to evaluate CD4-guided strategies for the prevention of opportunistic infections.