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Chulalongkorn Medical Journal

Abstract

Background: Diabetic foot ulcers (DFUs) affect 19-34% of diabetic patients lifetime, representing a major global health burden with over 18 million cases annually. The polymicrobial nature of DFU infections, combined with emerging antibiotic resistance genes, poses unprecedented clinical management challenges. Methicillin-resistant Staphylococcus aureus (MRSA) prevalence reaches 84% and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae exceeds 50% in some regions, creating urgent therapeutic concerns.

Objective(s): This comprehensive review examines current understanding of microbial communities in diabetic foot ulcers and their associated resistome, analyzing molecular mechanisms underlying antibiotic resistance and clinical implications to identify evidence-based management strategies.

Methods: A narrative review approach was employed using systematic literature searches in PubMed/MEDLINE, Embase, Web of Science, and Google Scholar databases from 2014-2025. Search strategies utilized MeSH terms including "diabetic foot ulcer," "antibiotic resistance genes," "microbiome," and "resistome.".

Result(s): Analysis revealed extensive resistome diversity with individual ulcers harboring dozens of distinct resistance determinants. Predominant resistance genes include mecA (methicillin resistance, 48.7-84%), blaCTX-M, blaSHV, blaTEM (ESBL production, 25.6-52.94%), and various fluoroquinolone resistance genes (qnrB, 47.74%). Horizontal gene transfer mechanisms facilitate rapid resistance dissemination within polymicrobial biofilm communities, significantly impacting treatment outcomes with 2-3 fold higher treatment failure rates.

Conclusion: Antibiotic resistance in diabetic foot ulcers represents a critical challenge requiring urgent multifaceted approaches. Future directions must prioritize rapid diagnostic technologies, precision antimicrobial approaches, and innovative therapeutic interventions including antimicrobial photodynamic therapy and bacteriophage treatment to address this growing threat.

DOI

10.56808/2673-060X.5708

First Page

INTRODUCTION Diabetic foot ulcers (DFUs) represent one of the most devastating complications of diabetes mellitus, affecting approximately 19-34% of diabetic patients during their lifetime and constituting a major global health burden with over 18 million cases annually worldwide (1,2). The economic impact is staggering, with direct healthcare costs reaching billions annually due to prolonged hospitalizations and surgical interventions. In contrast, five-year mortality rates following amputation reach 46-57%, comparable to aggressive cancers (3). The pathogenesis involves complex interactions between compromised immune function, peripheral neuropathy, and microvascular complications, creating microenvironments favoring polymicrobial communities and biofilm formation (4). These infections demonstrate remarkable resilience to antimicrobial therapy through synergistic bacterial interactions, quorum sensing, and metabolic cooperation (5). Antibiotic resistance has emerged as a critical threat, with methicillin-resistant Staphylococcus aureus (MRSA) prevalence reaching up to 84% and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae exceeding 50% in some regions (6,7). Horizontal gene transfer mechanisms facilitate rapid resistance dissemination within these polymicrobial communities, with individual ulcers harboring dozens of distinct resistance determinants (8,9). This review synthesizes current knowledge regarding antibiotic resistance genes in diabetic foot ulcer microbiomes, analyzing resistance mechanisms, clinical implications, and therapeutic strategies. The scope encompasses peer-reviewed literature from 2014 to 2025, focusing on molecular epidemiology studies and mechanistic investigations to address the urgent need for evidence-based approaches to combat resistance in this vulnerable population (10). METHODOLOGY This comprehensive narrative review was designed to provide an expert synthesis of current knowledge regarding antibiotic resistance genes in diabetic foot ulcer microbiomes. Rationale for Narrative Approach A narrative review approach was selected due to the diverse nature of this field, which encompasses molecular, clinical, and epidemiological studies that utilize fundamentally different methodologies unsuitable for meta-analysis. The rapidly evolving genomic technologies and resistance mechanisms require flexible evidence inclusion and expert interpretation to synthesize complex molecular mechanisms with clinical outcomes. Clinical

Last Page

Consent to participate Not applicable. Consent for publication The author reviewed the results and approved the final version of the manuscript. Authors' contributions The author confirms sole responsibility for all aspects of this work. Data availability All relevant data can be found within the manuscript. Competing interests The author declares that no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Supplementary Information The online version contains supplementary material. List of Abbreviations: AI: Artificial intelligence DFU: Diabetic foot ulcer ESBL: Extended-spectrum beta-lactamase HGT: Horizontal gene transfer MDR: Multidrug-resistant / Multidrug resistance MRSA: Methicillin-resistant Staphylococcus aureus MSSA: Methicillin-sensitive Staphylococcus aureus NGS: Next-generation sequencing PCR: Polymerase chain reaction PMQR: Plasmid-mediated quinolone resistance SCCmec: Staphylococcal cassette chromosome mec TMP-SMX: Trimethoprim-sulfamethoxazole XDR: Extensively drug-resistant

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