Nontraditional Antimicrobial Technologies and Combination Treatment Strategies to Address Antibiotic Resistance in Intra-abdominal Infections
Background
A narrative review argues that addressing antimicrobial resistance (AMR) in intra-abdominal infections (IAIs) requires considering both new drugs and nontraditional antimicrobial strategies. The researchers surveyed preclinical and clinical literature, examining the potential of different technologies and the barriers to clinical adoption. This was not a patient trial directly testing the efficacy of a specific combination treatment.
IAIs can accompany appendicitis or intestinal perforation, and choosing antimicrobials becomes more complicated when multiple bacterial species are involved. The distinctive drug-distribution environment of the peritoneal cavity also makes it difficult to apply treatments that have worked for other infections without modification. AMR is linked not only to treatment in human medicine but also to reservoirs of resistant bacteria in veterinary medicine, agriculture, and the environment. International responses have been pursued from a One Health perspective that considers the health of people, animals, and the environment together.
Key findings
The researchers reviewed new antibiotics and antimicrobial combinations, as well as alternatives that could complement existing antibiotics. The review included drugs approved for complicated intra-abdominal infections (cIAIs), drugs approved for other indications, clinical development candidates, and preclinical technologies. Evidence for agents discussed in the paper—including fluoroquinolones, beta-lactamase inhibitors, and polymyxin analogues—cannot all be interpreted as efficacy demonstrated in patients with IAIs.
Nontraditional antimicrobial alternatives are also being explored to reduce the risk of resistance emerging. Depending on their type, nanoparticles (NPs) can exert direct antimicrobial effects, such as damaging bacterial membranes, or serve as carriers for antibiotic delivery. Improved intraperitoneal bioavailability and reduced systemic toxicity were presented as potential benefits of these carriers. Antimicrobial peptides (AMPs) act on bacterial membranes, and some also interfere with intracellular processes. Their clinical adoption is constrained by degradation in bodily fluids, toxicity at high concentrations, and production costs.
Bacteriophages are viruses that infect specific bacteria. Evidence of reduced bacterial burden and improved survival has been reported in mouse models of peritonitis and intra-abdominal sepsis. The CRISPR/Cas system is being explored as a way to target specific genetic sequences to eliminate bacteria or remove resistance genes; antimicrobial treatment research in this area remains largely preclinical. Probiotics and microbiome-restoration strategies aim to restore gut microbial balance and the ability to prevent resistant bacteria from establishing themselves. They should not be interpreted as treatments that directly eliminate harmful bacteria in the peritoneal cavity.
There is hope that combining different mechanisms could reduce the emergence of resistance, but this effect has not been demonstrated across combination strategies as a whole. Bacteria can also develop resistance to phages through receptor mutations, so the effects of combination and sequential treatments need separate evaluation.
Implications and outlook
Challenges remain before new antimicrobial strategies can become established in clinical practice. Key issues include delivery technologies that can reliably carry therapeutic agents to the infection site, safety in living organisms, and meeting regulatory standards. Pharmacokinetic and pharmacodynamic data that reflect protein binding and changes in acidity in the peritoneal cavity also need to be strengthened. For approaches involving administration of live microorganisms, such as probiotics, safety in immunocompromised patients and critically ill surgical patients, along with strain-specific evidence of efficacy, requires careful assessment.
The researchers proposed integrating multiple treatment options on the basis of rapid diagnosis and appropriate antimicrobial use. However, the review did not conduct a quantitative meta-analysis, and cIAI-specific clinical trials are scarce, so some evidence was drawn from other infection models. The authors also acknowledged possible selection and author bias and underrepresentation of negative studies. Further trials assessing efficacy and safety in patients with cIAIs are needed to determine the clinical value of personalized combination treatments.
Source: Europe PMC full text of the review published in Antibiotics.
Antimicrobial resistance (AMR) among pathogens involved in intra-abdominal infections (IAIs) represents a critical and escalating clinical challenge. The interconnected nature of antimicrobial resistance, spanning human medicine, veterinary practice, agricultural use and environmental reservoirs, has required coordinated international responses based on the 'One Health' principle. This study presents an update on efforts underway worldwide to develop new antibiotics, novel combined antimicrobial agents, and alternatives to classic therapies for IAIs. New antibiotics or compounds with antibacterial activity are currently in various stages of clinical trials, including several fluoroquinolones, beta-lactamase inhibitors, and polymyxin analogues. To reduce the risk of bacterial resistance, various additions to antimicrobial treatments are being explored, such as nanoparticles (NPs), antimicrobial peptides (AMPs), bacteriophages, the CRISPR/Cas system, and probiotics. Each modality offers distinct mechanisms that circumvent established resistance pathways, including multi-target membrane disruption, sequence-specific gene editing, and microbiome restoration. Current preclinical and clinical evidence is synthesized, and key translational barriers, including delivery challenges, safety concerns, regulatory complexity, and the need for IAI-specific pharmacokinetic data are critically examined. In conclusion, the convergence of novel antibiotic agents and non-traditional antimicrobial strategies reviewed herein provides the foundation for a new paradigm in the management of drug-resistant IAIs. The transition from a monotherapy-centric approach to an integrated, multi-modal treatment framework, guided by rapid diagnostics and informed by antimicrobial stewardship, will be essential to preserve therapeutic efficacy against AMR threats of the coming decades.
The practical value of this review lies in distinguishing the levels of evidence and validation needs of treatment candidates for resistant intra-abdominal infections. For example, future clinical trials in patients with cIAIs in whom resistant bacteria have been identified could assess whether adding phages or antimicrobial peptides to existing antimicrobial treatment improves efficacy and safety, and whether intraperitoneal drug exposure is sufficient. Nanoparticle carriers should also be evaluated by distinguishing their direct antimicrobial activity from their drug-delivery function. These are research-design scenarios, not recommendations for combination prescriptions for current patients. For developers, the review identifies challenges in delivery stability, toxicity, manufacturing, and regulatory validation, but it does not demonstrate improved treatment success rates or the commercialization of personalized combination products.