Decolonizing the gut from multidrug-resistant bacteria: Current strategies and future perspectives

Table 1 Risk factors for acquiring multi-drug resistant bacteria

Category	Risk factor
Healthcare-associated	Prolonged hospitalization (especially in ICU). Recent surgery or invasive procedures. Use of medical devices (catheters, ventilators, central lines). Residence in long-term care facilities. Frequent hospital admissions or outpatient visits. Hemodialysis or chronic outpatient treatments
Antibiotic exposure	Prolonged use of broad-spectrum antibiotics. Inappropriate or incomplete antibiotic courses. Over-the-counter or self-medicated antibiotic use
Patient-related	Immunocompromised status (e.g., cancer, HIV, transplants). Chronic illnesses (e.g., diabetes, COPD, renal failure). Extremes of age (infants and elderly). Malnutrition. Gut dysbiosis due to prolonged gastric acid suppression
Environmental/community	International travel to high MDR prevalence regions. Contact with infected or colonized individuals. Poor sanitation or overcrowded living conditions

ICU: Intensive care unit; HIV: Human immunodeficiency virus; COPD: Chronic obstructive pulmonary disease; MDR: Multi-drug resistant.

Table 2 Different approaches for faecal microbiota transplantation

Approach	Method	Pros	Cons
Colonoscopy	Delivery of fecal material into the colon via a colonoscope	High success rate, allows direct placement in the colon	Invasive, requires bowel preparation, potential complications like perforation
Nasogastric/nasoenteric tube	Tube insertion through the nose into the stomach or small intestine for faecal infusion	Non-surgical, effective for small intestine delivery	Risk of aspiration, discomfort, nausea and vomiting
Capsule delivery	Freeze-dried faecal material in capsules taken orally	Non-invasive, convenient, avoids procedural risks	Requires multiple capsules, potential for reduced efficacy in some cases
Enema	Faecal material mixed with solution and introduced via the rectum	Simple, can be done at home, avoids invasive procedures	Lower retention time, may require multiple doses
Rectal infusion	Controlled delivery of faecal material into the rectum	Less invasive than colonoscopy, localized delivery	Requires professional administration, may not reach upper colon effectively

Table 3 Comparison between phage therapy and antibiotics

Feature	Phage therapy	Antibiotics
Mechanism of action	Targets and infects specific bacteria, leading to their lysis	Interferes with essential bacterial processes like cell wall or protein synthesis
Host specificity	Highly specific—usually affects only certain strains and species	Broad spectrum—may act on various bacterial species
Resistance development	Bacteria can develop resistance, but phages may co-evolve	Resistance is a growing issue, and development of new antibiotics is slow
Impact on microbiota	Minimal disruption to beneficial microbiota	Can disrupt gut flora, leading to dysbiosis or secondary infections like Clostridioides difficile infection
Replication in host	Multiplies at the infection site if host bacteria are present	Does not self-replicate; efficacy depends on dosage
Immunogenicity	May trigger immune response, especially with repeated use	Less likely to elicit strong immune reactions
Production and customization	Can be tailored to target specific pathogens	Mass-produced with fixed formulations
Environmental impact	Generally considered eco-friendly	Overuse can contribute to antibiotic resistance and gut dysbiosis

Table 4 Challenges and potential solutions in phage therapy

Challenge	Description	Potential solutions
Narrow host range	Phages are highly specific, targeting only a limited range of bacterial strains	Develop phage cocktails targeting multiple strains
Bacterial resistance development	Bacteria may evolve resistance to phages, just like with antibiotics	Using phage combinations or cocktails; engineer phages to overcome resistance
Immunogenicity of phages	The human immune system may neutralize phages, limiting their effectiveness	Use encapsulation techniques (e.g., liposomes) to shield phages; select less immunogenic phages
Phage clearance by organs	The liver and spleen may rapidly clear phages from the bloodstream	Modifications in phages to evade immune detection; optimize dosing regimens to maintain therapeutic levels
Horizontal gene transfer risk	Temperate phages can transfer harmful genes (e.g., toxin or resistance genes) between bacteria	Prefer strictly lytic phages over temperate ones; genetically screen and engineer phages for safety
Storage and stability	Phages can lose viability due to improper storage conditions	Optimize formulations and storage conditions (e.g., lyophilization, buffer systems) for stability
Lack of standardized regulations	Absence of global guidelines makes approval and clinical use challenging	Developing common regulatory frameworks; global collaborations on phage therapy policies
Limited clinical trials	Few large-scale, randomized controlled trials exist to validate efficacy and safety	Encourage funding and support for rigorous clinical studies to build evidence for medical approval

Table 5 Summary of the methods for gut decolonization

Method	Mechanism/strategy	Current status/potential	Limitations
Synbiotics (Prebiotics + Probiotics)	Combination approach to feed beneficial bacteria and inhibit pathogen growth	Evidence for Clostridioides difficile; under evaluation for broader MDRO decolonization	Strain/pathogen-specific efficacy; low to moderate benefits only; inconsistent results across trials
Live biotherapeutic products	Consortia of beneficial bacteria designed to displace pathogens and modulate immunity	Examples include VE707; under investigation for MDROs	Mostly preclinical; unclear long-term effects; regulatory challenges for approval
Selective digestive decontamination	Use of non-absorbable oral and systemic antibiotics to decolonize gut MDROs	Used in ICU settings; variable evidence; some success in ESBL-E decolonization	Promotes resistance (e.g., colistin-resistant strains); disrupts microbiota; lacks standardized protocols
Fecal microbiota transplantation	May restore healthy microbiota to compete MDROs	Successful in small studies; ongoing trials for CRE, VRE. Requires standardization and safety screening	Risk of transferring ARGs; labor-intensive donor screening; cold-chain dependency
Bacteriophage therapy	Phages specifically target and lyse pathogenic strains without affecting commensals	Promising; several preclinical and early clinical studies underway. Challenges include phage resistance and regulatory issues	Narrow host range; potential phage resistance; immunogenicity; storage and regulatory hurdles
CRISPR-Cas system	Use of gene-editing tools to selectively target and eliminate resistance genes	Under experiment, promising specificity and minimal off-target effects	Delivery method challenges; early-stage development; ethical and safety concerns

MDRO: Multi-drug resistant organisms; ICU: Intensive care unit; ESBL: Extended spectrum beta-lactamases; CRE: Carbapenem resistant enterobacteriaceae; VRE: Vancomycin resistant enterococcus; ARG: Antibiotic resistant.