Evaluation of Antibiotic Impact on Microbiota and Resistance Genes in ESBL and VRE Carriers Using Ciprofloxacin and Vancomycin

The primary objective of this study is to evaluate the dynamics of **carriage** of resistant bacteria, specifically Extended-Spectrum Beta-Lactamase (ESBL) and Vancomycin-Resistant Enterococci (VRE), upon the introduction of an antibiotic challenge. This is clinically relevant as understanding these dynamics can inform treatment strategies and help mitigate the spread of antibiotic-resistant infections, which pose significant challenges in healthcare settings.

Secondary objectives include evaluating changes in the composition of the intestinal flora during the administration of antibiotics. This is important for understanding the broader impact of antibiotic treatment on gut microbiota, which can have implications for patient health and the development of resistance.

The clinical trial involves a study population comprising both **male** and **female** participants, aged 18 years and older. The trial focuses on individuals with a verified carriage of **Vancomycin-Resistant Enterococci (VRE)** or **Extended-Spectrum Beta-Lactamase (ESBL)** producing bacteria, with a specific requirement for EPE carriers to have isolates resistant to ciprofloxacin. Participants are required to have tested negative in the latest screening for VRE/EPE. The trial does not include a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits are not specified. The sponsor has not provided information regarding the total number of participants in the study. Key inclusion criteria include signed consent and adequate contraception for fertile women, as recommended by the CTFG. The selection process for the trial population is not detailed in the available data.

The clinical trial is designed to evaluate the dynamics of **resistant bacteria** carriage upon the introduction of an antibiotic challenge. This study is a randomized, double-blind, controlled trial, focusing on individuals with verified carriage of **Vancomycin-Resistant Enterococci (VRE)** or **Extended-Spectrum Beta-Lactamase (ESBL)** producing bacteria. The trial will utilize two antibiotics, **Ciprofloxacin** and **Vancomycin**, administered orally in the form of film-coated tablets and hard capsules, respectively. The maximum daily dose for Ciprofloxacin is 1000 mg, with a total dose not exceeding 5000 mg over a 5-day period. For Vancomycin, the maximum daily dose is 500 mg, with a total dose not exceeding 2500 mg over the same duration. The trial is expected to conclude by September 30, 2026, with recruitment having commenced on February 6, 2023.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed through signed consent, age verification (over 18 years), and confirmation of VRE/ESBL carriage. The inclusion criteria also require negativity in the latest screening for VRE/EPE and resistance to Ciprofloxacin for EPE carriers. Adequate contraception is required for fertile women. The primary endpoint is the transition from negative to positive fecal screen for VRE/EPE directly after the antibiotic challenge, with secondary endpoints including the time to revert to negative carriage and changes in microbiota composition. Follow-up visits will monitor these transitions and assess the microbiota's return to baseline.

The expected length of participant involvement is determined by the treatment period, which is a maximum of 5 days, followed by necessary follow-up visits until the study's end. Conditions that may lead to early termination from the study include adverse reactions to the antibiotics or withdrawal of consent by the participant. The trial's design ensures rigorous monitoring and data collection to achieve its objectives, contributing valuable insights into the impact of antibiotic treatment on resistant bacteria carriage.

The clinical trial involves the administration of **Ciprofloxacin**, an antibiotic used to evaluate the dynamics of resistant bacteria carriage upon antibiotic challenge. **Ciprofloxacin** is provided in the form of a film-coated tablet, with a chemical origin of the active substance. The maximum daily dose is 1000 mg, with a total maximum dose of 5000 mg over a treatment period of up to 5 days. The route of administration is oral, and the medication is not formulated for pediatric use. Compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen.

Additionally, the trial includes the use of **Vancomycin**, another antibiotic, to further assess the impact on the normal flora and resistance gene presence in carriers of ESBL and VRE. **Vancomycin** is administered as a hard capsule, also with a chemical origin of the active substance. The maximum daily dose is 500 mg, with a total maximum dose of 2500 mg over a 5-day treatment period. The administration route is oral, and similar to **Ciprofloxacin**, it is not intended for pediatric use. Participant compliance is monitored to ensure accurate adherence to the dosing schedule.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints include the transition from negative to positive fecal screen for **Vancomycin-resistant Enterococci (VRE)** or Extended-spectrum beta-lactamase (EPE) directly after the antibiotic challenge, as well as differences in the microbiota's composition and diversity compared to before the antibiotic challenge. Secondary endpoints will evaluate the time required for participants who transitioned from negative to positive VRE/EPE carriage to revert to negative, the time for the intestinal microbiota's composition and diversity to return to baseline, and differences in resistance detection using conventional methods compared to metagenomic methods, defined as discordant results.