Aleksandar Nikolić

Background: Ventilator-associated pneumonia (VAP) is a common and serious nosocomial infection in mechanically ventilated preterm infants and is increasingly caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative organisms. Tigecycline, a glycylcycline with broad activity against many such pathogens, is not approved below 18 years of age and carries a boxed warning for excess mortality that is most pronounced in hospital-acquired and ventilator-associated pneumonia. Its role, if any, in preterm infants with VAP is undefined. Objectives: To systematically identify and appraise all human evidence on the efficacy (clinical cure, microbiological eradication, survival) and safety (adverse events, mortality) of tigecycline used to treat VAP or nosocomial pneumonia during mechanical ventilation in preterm infants and neonates. Methods: A PRISMA 2020 structured search of PubMed/MEDLINE, Cochrane CENTRAL, Scopus, trial registries, regulatory documents, Google Scholar and reference lists was designed without language or date restrictions. Eligible reports described tigecycline treatment of pneumonia/VAP in neonates or young infants; pediatric case series and syntheses were retained as contextual evidence. Because only case reports and small non-comparative series were anticipated, a narrative synthesis was pre-specified; JBI tools and GRADE were planned for appraisal and certainty. Results: No randomized controlled trial, controlled observational study, or study dedicated to tigecycline for VAP in preterm infants was identified. Direct evidence meeting the full eligibility criteria (preterm neonate, VAP specifically, separately extractable outcomes) was limited to two case reports of extremely preterm neonates with VAP successfully weaned after tigecycline-based salvage combination therapy. Six further neonatal/young-infant reports initially considered were, on full-text re-review, reclassified as contextual (not index) evidence because they described non-VAP infections (sepsis, or CNS infections such as ventriculitis/meningitis), non-preterm ages, or mixed-infection series without separable VAP data. Reported outcomes were generally favorable in published cases but are subject to severe selection and publication bias; thrombocytopenia, hypofibrinogenemia and hepatic enzyme elevation were the principal adverse signals, against a class-level mortality signal concentrated in VAP. Quantitative pooling was not appropriate. The overall certainty of evidence was very low. Conclusions: There is no direct, credible efficacy or safety evidence supporting tigecycline for VAP in preterm infants. Available data neither establish benefit nor exclude harm. Based on this very-low-certainty evidence and on regulatory/class-level safety data rather than on demonstrated efficacy, tigecycline warrants consideration only as a last-resort, combination salvage option for culture-confirmed pan- or extensively drug-resistant pathogens when no safer alternative exists, with intensive monitoring and, ideally, within a registry or trial. Adequately designed neonatal pharmacokinetic and comparative safety studies are urgently needed. Registration: PROSPERO CRD420261450972 (registered 14 July 2026).

Introduction: Permissive hypercapnia has become an integral component of lung-protective ventilation strategies during one-lung ventilation (OLV), particularly in thoracic surgery. Its potential immunomodulatory effects have attracted increasing interest; however, clinical evidence remains limited and inconsistent. The Aim: The primary objective was to evaluate the effects of permissive hypercapnia on inflammatory biomarkers in bronchoalveolar lavage fluid and serum during one-lung ventilation. The secondary objective was to assess the influence of different ventilation modes on these inflammatory responses. Methods: Forty patients undergoing elective lung surgery requiring OLV were prospectively enrolled and allocated to either a normocapnic (n = 20) or hypercapnic group (n = 20). BAL concentrations of TNF-α, IL-1β, IL-6, and IL-8 were measured before and after intervention. Serum IL-6, C-reactive protein (CRP), and leukocyte counts were also assessed. Outcome Measures: Primary outcome: Change in bronchoalveolar lavage (BAL) levels of preselected biomarkers for inflammation (TNF-α, IL-1β, IL-6, and IL-8) and in serum (IL-6, CRP, and WBC) between the normocapnic and hypercapnic groups during one-lung ventilation. Secondary outcome: Whether the inflammatory response differed according to the ventilation mode (pressure-controlled versus volume-controlled ventilation). Results: Baseline and post-intervention BAL concentrations of TNF-α, IL-1β, IL-6, and IL-8 were generally comparable between the hypercapnic and normocapnic groups. No significant differences were observed in post-intervention BAL concentrations of TNF-α, IL-1β, or IL-6 among the ventilated subgroups. However, post hoc analysis demonstrated significantly lower IL-8 concentrations in the hypercapnic-PC subgroup compared with the normocapnic-PC subgroup (p = 0.034). Within the normocapnic cohort, BAL IL-8 concentrations were significantly higher in the PC subgroup than in the VC subgroup (p = 0.012). In serum, postoperative IL-6 concentrations were significantly higher in the hypercapnic than in the normocapnic group (p = 0.003). Conclusions: Permissive hypercapnia was not associated with a reduction in BAL concentration of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8. However, postoperative serum IL-6 concentrations were significantly higher in patients exposed to hypercapnia. As the duration of surgery, one-lung ventilation, and mechanical ventilation was longer in the hypercapnic group, the observed increase in serum IL-6 cannot be attributed solely to hypercapnia. Further large-scale randomized studies are required to clarify the immunological effects of permissive hypercapnia during thoracic surgery.

Background: Patients with malignant diseases receiving chronic opioid therapy are particularly susceptible to drug–drug interactions because of extensive polypharmacy, multimodal anticancer treatment, supportive care, and comorbidities. This study aimed to determine the prevalence of potentially clinically relevant drug–drug interactions and to identify factors associated with their occurrence. Methods: This exploratory observational cross-sectional pilot study included 49 adult oncology patients receiving chronic opioid therapy. Complete medication regimens were screened using the Medscape Drug Interaction Checker and Lexicomp. Lexicomp category D and X interactions were analysed descriptively. Because category D interactions were nearly universal and category X interactions were rare, the presence of at least one Medscape “Serious—Use Alternative” interaction was used pragmatically as the binary outcome for regression modelling. Potential predictors were assessed using univariable binary logistic regression and a parsimonious adjusted model with covariates selected using a clinically informed approach. Because of quasi-complete separation, Firth’s penalized-likelihood logistic regression was used as the primary adjusted analysis. Results: Lexicomp category D interactions were identified in 48 of 49 patients (98.0%), whereas category X interactions were present in 2 patients (4.1%). Medscape serious interactions were detected in 33 patients (67.3%). In the Firth-adjusted model, female sex was associated with lower odds of a Medscape serious interaction (adjusted OR 0.12, 95% CI 0.02–0.52), while cardiovascular disease was associated with higher odds (adjusted OR 5.16, 95% CI 1.27–26.31). Stage IV disease showed a positive but statistically non-significant association, and total medication count was not independently associated with the outcome in sensitivity analysis. Because of the small pilot sample and the resulting wide confidence intervals, these findings should be interpreted as exploratory and hypothesis-generating. Conclusions: Oncology patients receiving chronic opioid therapy had a high burden of potentially clinically relevant drug–drug interactions, predominantly Lexicomp category D interactions, warranting consideration of therapy modification and individualized monitoring rather than absolute avoidance. Regular medication review, use of complementary interaction databases, and individualized clinical assessment may improve pharmacotherapy safety in this vulnerable population.