Abstract
(1) Background: Zinc is an essential micronutrient involved in immune regulation, epithelial barrier integrity, and the host response to bacterial infections. However, the clinical benefits of zinc supplementation across different age groups remain uncertain, with heterogeneous findings and variable dosing strategies reported in the literature. (2) Objectives: To map and summarize randomized controlled trials (RCTs) evaluating zinc supplementation (either as treatment or prophylaxis) for bacterial infection outcomes in neonates, children, and adults, and to identify gaps requiring further research, including the use of zinc-based nanoparticles. (3) Eligibility Criteria: We included English-language RCTs that evaluated zinc supplementation and reported clinical outcomes related to bacterial infections. Observational studies, trials without infection-related outcomes, and studies not involving human participants were excluded. (4) Sources of Evidence: A MEDLINE (PubMed) search was conducted from 2000 to 1 November 2025 using predefined keywords related to zinc supplementation, neonates, children, adults, and bacterial infections. Reference lists of eligible articles were screened to identify additional studies. (5) Charting Methods: Data were charted for each included study, including population characteristics, zinc dosing and regimen, type of supplementation (therapeutic or prophylactic), main infection-related outcomes, and key findings. Data charting was performed independently and verified within the research team. (6) Results: A total of 51 RCTs were included: 10 in neonates, 32 in children, and 9 in adults. In neonates, therapeutic zinc supplementation as an adjunct to antibiotics showed heterogeneous results, with some studies reporting reductions in morbidity, inflammatory markers or mortality, while others found no significant differences in clinical outcomes. In children, zinc supplementation consistently reduced the duration and severity of diarrheal episodes and, in several trials, improved the resolution of respiratory infections. In adults, the evidence was limited but suggested potential benefits in selected populations, such as burn patients or those with zinc deficiency or immunologic dysfunction. Variability in zinc dosage, treatment duration, and outcome definitions limits direct comparison across studies. (7) Conclusions: Zinc supplementation appears to provide benefits in neonates and children, whereas evidence in adults remains mixed and inconclusive. Standardized, well-powered RCTs are needed to define optimal dosing strategies, identify populations most likely to benefit, and clarify the mechanisms underlying zinc's anti-infective effects. Future research should consider the use of zinc oxide nanoparticles (ZnO-NPs) demonstrated broad-spectrum antimicrobial activity and potential synergy with antibiotics, although clinical data remain still limited.