Timothy Arthur Chandos Snow

Background: Post-operative infections are a significant cause of morbidity in patients undergoing major elective surgery. Peri-operative antibiotics are used to reduce the risk of infection. Several antibiotics modulate the host immune response. Objectives: Our objective was to determine the ex vivo immunomodulatory properties of commonly used antibiotics (amoxicillin, cefuroxime, metronidazole, or combined cefuroxime–metronidazole) on monocyte and lymphocyte phenotypes in patients undergoing major elective surgery. Methods: We performed a prospective cohort study of patients aged ≥18 years admitted to the post-anaesthetic care unit following major elective non-cardiac surgery. Peripheral blood mononuclear cells isolated immediately after surgery were incubated with antibiotics with or without a monocyte (heat-killed E. coli) or lymphocyte (CD3/CD28 beads) stimulus ex vivo. Immune cell phenotype was characterised using flow cytometry. Results: Twenty-eight patients were included. All antibiotics tested were associated with a reduction in T-cell viability, and changes to monocytes were minimal. Among CD4⁺ and CD8⁺ lymphocytes, cefuroxime increased IFN-γ (at low and high doses) and increased CD4⁺ lymphocyte IL-2 and IL-2R at higher doses. Among CD4⁺ lymphocytes, at both doses, cefuroxime increased %T_h1 population, with a parallel decrease in %T_h2, %T_h17, IL-17A, FOX-P3, and T-bet. Among the T_h1 sub-population, changes were seen at higher cefuroxime doses, including increased viability and PD-1, and a decrease in FAS, IFN-γ and CD28, and IL-7R expression. Conclusions: The choice of antibiotics directly impacts immune function following major surgery, with cefuroxime associated with ex vivo immunomodulatory effects on CD4⁺ lymphocytes. The functional implications on the development of subsequent post-operative infectious complications and long-term cancer-free survival require further investigation.

Antibiotics are the fundamental treatment for bacterial infections. However, they are associated with numerous side effects. Their adverse effects on the immune system are increasingly recognised, with several mechanisms identified. In this review, we focus on their direct effects on cellular immunity. We review the effects of antibiotics on mitochondrial function and how they impair specific immune cell functions including chemotaxis, phagocytosis, cytokine production, antigen presentation, and lymphocyte proliferation. Findings are described in a multitude of in vivo and in vitro models. However, their impact on patient immunity and clinical outcomes requires further research. Awareness of the potential adverse effects of antibiotics may improve antimicrobial stewardship. The use of therapeutic drug monitoring may help to reduce dose-dependent effects, which warrants further research.

Purpose Interleukin-6 (IL-6) levels discriminate between patients with mild and severe COVID-19, making IL-6 inhibition an attractive therapeutic strategy. We conducted a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of randomized-controlled trials to ascertain the benefit of IL-6 blockade with tocilizumab for COVID-19. Methods We included randomized-controlled trials (RCTs) allocating patients with COVID-19 to tocilizumab. Our control group included standard care or placebo. Trials co-administering other pharmacological interventions for COVID-19 were not excluded. Primary outcome was 28–30 day mortality. Secondary outcomes included progression-to-severe disease defined as need for mechanical ventilation, intensive-care unit (ICU) admission, or a composite. Results We identified 10 RCTs using tocilizumab, 9 of which reported primary outcome data (mortality), recruiting 6493 patients with 3358 (52.2%) allocated to tocilizumab. Tocilizumab may be associated with an improvement in mortality (24.4% vs. 29.0%; OR 0.87 [0.74–1.01]; p = 0.07; I² = 10%; TSA adjusted CI 0.66–1.14). Meta-regression suggested a relationship between treatment effect and mortality risk, with benefit at higher levels of risk (logOR vs %risk beta = −0.018 [−0.037 to −0.002]; p = 0.07). Tocilizumab did reduce the need for mechanical ventilation and was associated with a benefit in the composite secondary outcome but did not reduce ICU admission. Conclusions For hospitalized COVID-19 patients, there is some evidence that tocilizumab use may be associated with a short-term mortality benefit, but further high-quality data are required. Its benefits may also lie in reducing the need for mechanical ventilation.

We present a case of a 33-year-old woman in her third pregnancy diagnosed with platelet storage pool disorder who had previously suffered two postpartum major obstetric haemorrhages. Platelet storage pool disorder is a rare bleeding disorder where the platelet count is normal but platelet function is impaired due to deficiency of dense granules. A peripartum plan devised by an extensive multi-disciplinary team using principles for managing other bleeding and platelet function disorders helped minimise her risk of major haemorrhage. We also describe how point-of-care thromboelastography can help guide management and enable an individualised risk-benefit discussion with the woman about her anaesthetic choices.

Objective: The objective of this study was to conduct a meta-analysis and trial sequential analysis (TSA) of published randomized controlled trials (RCTs) to determine whether mortality benefit exists for extracorporeal blood purification techniques in sepsis. Data Sources: A systematic search on MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for RCTs was performed. Study Selection: RCTs investigating the effect of extracorporeal blood purification device use on mortality among critically ill septic patients were selected. Data Extraction: Mortality was assessed using Mantel-Haenszel models, and I² was used for heterogeneity. Data are presented as odds ratios (OR); 95% confidence intervals (CIs); p values; I². Using the control event mortality proportion, we performed a TSA and calculated the required information size using an anticipated intervention effect of a 14% relative reduction in mortality. Data Synthesis: Thirty-nine RCTs were identified, with 2,729 patients. Fourteen studies used hemofiltration (n = 789), 17 used endotoxin adsorption devices (n = 1,363), 3 used nonspecific adsorption (n = 110), 2 were cytokine removal devices (n = 117), 2 used coupled plasma filtration adsorption (CPFA) (n = 207), 2 combined hemofiltration and perfusion (n = 40), and 1 used plasma exchange (n = 106). On conventional meta-analysis, hemofiltration (OR 0.56 [0.40–0.79]; p < 0.001; I² = 0%), endotoxin removal devices (OR 0.40 [0.23–0.67], p < 0.001; I² = 71%), and nonspecific adsorption devices (OR 0.32 [0.13–0.82]; p = 0.02; I² = 23%) were associated with mortality benefit, but not cytokine removal (OR 0.99 [0.07–13.42], p = 0.99; I² = 64%), CPFA (OR 0.50 [0.10–2.47]; p = 0.40; I² = 64%), or combined hemofiltration and adsorption (OR 0.71 [0.13–3.79]; p = 0.69; I² = 0%). TSA however revealed that based on the number of existing patients recruited for RCTs, neither hemofiltration (TSA-adjusted CI 0.29–1.10), endotoxin removal devices (CI 0.05–3.40), nor nonspecific adsorption devices (CI 0.01–14.31) were associated with mortality benefit. Conclusion: There are inadequate data at present to conclude that the use of extracorporeal blood purification techniques in sepsis is beneficial. Further adequately powered RCTs are required to confirm any potential mortality benefit, which may be most evident in patients at greatest risk of death.