Clinical efficacy, safety, and pharmacologic determinants of antimicrobial peptides: A systematic review and meta-analysis

Abstract

Introduction: Antimicrobial resistance poses an escalating global health threat, driving the need for alternative therapeutic strategies beyond conventional antibiotics. Despite extensive preclinical research, the clinical performance of these agents remains incompletely characterized.

Objective: This systematic review and meta-analysis synthesize and evaluate clinical efficacy, safety, and pharmacologic determinants of antimicrobial peptide therapeutics in human studies, and determine their comparative performance against standard-of-care treatments.

Methods: A comprehensive search of PubMed, Embase, Web of Science, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform identified eligible clinical studies published between January 2000 and January 2026. Randomized controlled trials and comparative clinical studies reporting clinical or microbiologic outcomes were included in the quantitative meta-analysis. Early-phase, single-arm, or non-comparative studies were synthesized qualitatively. A random-effects model was used to estimate pooled risk ratios (RRs) for clinical cure, and heterogeneity was assessed using the I² statistic.

Results: Six comparative clinical studies involving 1,418 participants were included in the meta-analysis. Pooled analysis demonstrated no statistically significant difference in clinical cure between peptide-based therapeutics and standard-of-care treatments (RR 1.06, 95% confidence interval: 0.97-1.17), with moderate heterogeneity (I² = 64.7%). Early-phase and single-arm studies reported high clinical cure rates, particularly in biofilm-associated or localized infections. Subgroup analyses indicated that topical or locally-administered peptides produced more consistent therapeutic outcomes, whereas systemic administration showed greater variability and was more frequently limited by toxicity.

Conclusion: Antimicrobial peptides demonstrate promising activity in specific clinical contexts, particularly biofilm-related and drug-resistant infections. While current evidence does not show superiority over standard-of-care therapies, early-phase data highlight their potential in niche indications. Future development should prioritize optimizing therapeutic index, improving targeted delivery strategies, and designing infection-specific clinical trials to fully realize the clinical potential of this emerging therapeutic class.

Keywords

Antimicrobial peptides / Antimicrobial resistance / Biofilm-associated infections / Drug-resistant bacteria / Clinical trials

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