Evaluation of an Antibiotic Regimen Pharmacokinetic Applicable to Enterococcus Faecalis Infective Endocarditis

Infectious Endocarditis Clinical Trial

Official title:

Phase II Clinical Trial to Evaluate an Antibiotic Regimen Pharmacokinetic Applicable to Outpatient Parenteral Antimicrobial Therapy in Enterococcus Faecalis Infective Endocarditis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03681431
• Other study ID #: ENDOKINETIC-CEF
• Status: Completed
• Phase: Phase 2
• Start date: April 23, 2018
• Est. completion date: May 23, 2019

Study information

• Verified date: April 2024
• Source: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The clinical trial is designed as a phase II, crossover clinical trial. It will be carried out in healthy volunteers, who will receive two different antibiotic regimen based on ceftriaxone. One of the regimens had shown clinical effectiveness in this scenario, but it is not suitable for OPAT programs. In the other hand, a new treatment schema useful in OPAT programs is proposed, but there is still a lack of pharmacokinetic data to support it. The plasma drug concentrations will be measured in both cases, comparing the minimal drug concentration observed and the pharmacokinetic profiles of the two regimens.

Description:

Infective endocarditis (IE) is an uncommon but virulent infection disease. One of the most frequent etiology for this infection is Enterococcus faecalis. IE treatment is difficult due to the characteristics of the infection itself, the bacterial species and the frequent comorbidities of the patients. A bactericidal antimicrobial treatment is mandatory for the resolution of this disease, but most antibiotics do not exhibit this effect against E. faecalis and have prompted the combination of an aminoglycoside and a cell-wall active agent (generally a β-lactam) as the standard treatment. This is a lengthy treatment (4-6 weeks) and its primary side effect is nephrotoxicity. Furthermore, aminoglycoside resistant strain's rates are increasing in USA and Europe, getting more complicated to establish an effective antibiotic regimen. Nowadays, patients with E. faecalis IE are old and often have significant underlying comorbidities with an increased risk of developing nephrotoxicity with aminoglycoside treatment. For this reason, and for the relevance of high-level aminoglycoside-resistant strains, some alternatives have been explored. A double β-lactam regimen is an option, despite the intrinsically resistance of E. faecalis to cephalosporins. The most studied combination is a regimen based on ampicillin plus ceftriaxone, which has shown a synergistic effect in vitro. This combination is as effective as ampicillin plus gentamycin, but with lower nephrotoxicity. Those patients need at least 4-6 weeks of treatment with a prolonged hospitalization. However, after 2 week of treatment some patients are clinically stabilized and could be benefit of an outpatient parenteral antibiotic therapy (OPAT) program. For that purpose, it is essential to design a treatment regimen, which ensures the effectiveness and safety of the treatment, based on stability and pharmacokinetic and pharmacodynamics (PK/PD) studies of the administered drugs. Furthermore, the logistic and schedule should be simple enough to enable the inclusion in an OPAT program. In order to design an antibiotic regimen suitable for OPAT programs and as effective as the standard therapies for E. faecalis IE, we decided to start clinical trial.

The clinical trial is designed as a phase II, crossover clinical trial. It will be carried out in healthy volunteers, who will receive two different antibiotic regimen based on ceftriaxone. One of the regimens had shown clinical effectiveness in this scenario, but it is not suitable for OPAT programs. In the other hand, a new treatment schema useful in OPAT programs is proposed, but there is still a lack of pharmacokinetic data to support it. The plasma drug concentrations will be measured in both cases, comparing the minimal drug concentration observed and the pharmacokinetic profiles of the two regimens.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: May 23, 2019
• Est. primary completion date: April 23, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

Inclusion Criteria:

1. Male and female adults subjects.

2. Weight between 40 and 105 kilograms, both included, and body mass index lower than 34 kilograms per square meter.

3. The subject (or his/her "trusted representative") must have given his/her informed and signed consent approved by an Ethical Committee.

4. The subject must have normal analytical values or abnormal without clinical significance of biochemical parameters, liver and kidney function panel test, hemogram and album level. A medical check will be run by workers of Infectious Diseases Department.

5. The subject must have a normal physical examination or abnormal without clinical significance. A medical check will be run by workers of Infectious Diseases Department.

6. The medication taken usually by the subjects will be check by the Pharmacy Department in order to find possible interactions with ceftriaxone.

Exclusion Criteria:

1. Subjects with clinically significant abnormalities in laboratory test or physical exploration. A medical check will be run by workers of Infectious Diseases Department.

2. Subjects undergoing an active infection find at the screening.

3. Subjects with any clinical or surgery condition which contraindicate his/her inclusion, check by workers of Infectious Diseases Department.

4. Subjects who has received treatment with cephalosporins 21 days before the trial starts or during the trial (apart from the protocol treatment).

5. Subjects hypersensitive or allergic to cephalosporines or penicillins.

6. Subjects undergoing chronic or acute cutaneous diseases which prevent the treatment administration.

7. Subjects not giving his/her informed and signed consent approved by an Ethical Committee.

Related Conditions & MeSH terms

• Communicable Diseases
• Endocarditis
• Endocarditis, Bacterial
• Infections
• Infectious Endocarditis

Intervention

Drug:
• Ceftriaxone 4g/ 24h
Each individual will be administrated 2 doses of 2 g of ceftriaxone separated for 12 hours. After a wash-out period (5-7 days) the same individuals will receive a single dose 4 g of ceftriaxone. In both cycles, plasma drug concentrations will be measure during 24 hours.
• Ceftriaxone 2g/ 12h
Each individual will be administrated 2 doses of 2 g of ceftriaxone separated for 12 hours. After a wash-out period (5-7 days) the same individuals will receive a single dose 4 g of ceftriaxone. In both cycles, plasma drug concentrations will be measure during 24 hours.

Locations

Country	Name	City	State
Spain	University Hospital Virgen del Rocio	Sevilla

Sponsors (1)

Lead Sponsor	Collaborator
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum levels after 24 hours	To determinate whether 24 hours after the administration of 4 grams of ceftriaxone in a single short infusion, serums levels would be higher than 5 micrograms per millilitre	24 hours
Secondary	AUC 24 hours	To compare the 24 hours area under the curve (AUC) after the administration of 4 grams of ceftriaxone in a single short infusion and the administration of 2 grams of ceftriaxone in a two short infusions separated for 12 hours.	24 hours
Secondary	Plasma Clearance	To determinate ceftriaxone plasma clearance after the administration of 4 grams of ceftriaxone in a single short infusion.	24 hours
Secondary	Elimination Half-life	To determinate ceftriaxone elimination half-life after the administration of 4 grams of ceftriaxone in a single short infusion.	24 hours
Secondary	Volume of Distribution	To determinate ceftriaxone volume of distribution after the administration of 4 grams of ceftriaxone in a single short infusion.	24 hours
Secondary	Maximum Plasma Concentration	To determinate ceftriaxone maximum plasma concentration after the administration of 4 grams of ceftriaxone in a single short infusion.	24 hours
Secondary	Safety: Number, frequency and importance of adverse reactions.	To determinate the safety (number, frequency and importance of adverse reactions) of the administration of 4 grams of ceftriaxone in a single short infusion	1 month