Clinical trial NCT04171674: Pharmacokinetics of High-dose Ceftobiprole in Community-acquired Pneumonia Under Mechanical Ventilation.
Official title: A Study on Plasma and Pulmonary Pharmacokinetics of High-dose Ceftobiprole Given by Continuous Infusion in Mechanically-ventilated Adult Patients With Severe Community-acquired Pneumonia
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Pneumonia
Keywords: community-acquired pneumonia
Lead sponsor: Centre Hospitalier Universitaire de Nīmes
Sponsor class: OTHER
Collaborators: name: Centre Hospitalier Lyon Sud
name: Hôpital Haut-Lévêque
First posted: 2019-11-21
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The main aim of the study is to describe plasma pharmacokinetics (PK) and pulmonary diffusion of high-dose ceftobiprole (500 mg loading dose followed by 2.5 g under continuous infusion for 24h) for mechanically-ventilated adult patients with severe community-acquired pneumonia, using population PK modelling.

The secondary aims are :

A- To determine whether the pharmacokinetic / pharmacodynamic (PK/PD) targets can be achieved in the plasma and epithelial lining fluid with the recommended doses of ceftobiprole.

B- To define the optimal dose regimen for ceftobiprole in this population.

C- To evaluate clinical recovery (at Day 3 and Day 8) and microbiological recovery (at Day 3).

D- To evaluate the clinical evolution.

E- To evaluate the clinical and biological tolerance.

Detailed description: Pneumonia is still associated with high morbi-mortality, and rapid treatment with suitable antibiotics is required, i.e. with a broad enough spectrum to cover the activity of all the potentially-incriminated pathogens. These antibiotics must be administered at efficient doses and diffused in sufficient quantity at the infection site.

Unlike other beta-lactams, ceftobiprole is a new-generation broad-spectrum cephalosporin which is active on the majority of pathogens encountered in acute, community-acquired pneumonia (CAP) and also on methicillin-resistant staphylococcus aureus (MRSA) and non-fermenting Gram-negative bacilli (GNB) like pseudomonas aeruginosa. It is indicated for the treatment of CAP and also healthcare-associated pneumonia, other than that acquired under mechanical ventilation.

For any antibiotic administered to critically ill patients it is necessary to ensure that the pharmacokinetic/pharmacodynamic (PK/PD) targets correlated with clinical efficacy can be reached with the recommended doses. The DALI study published in 2014 was the first study to alert on the risk of plasma under-dosing when the standard doses of beta lactams were administered in severely ill patients.

Since then, several PK studies performed in the intensive care unit have confirmed the significant risk of non-optimal doses in this population, linked to physiopathological alterations caused by sepsis. So far there have been no studies specifically aimed at the pharmacokinetics of ceftobiprole in those patients with CAP requiring mechanical ventilation. Furthermore, although there is increasing use in the pharmaceutical industry and in the post-developmental phases of medicines, a population PK analysis to help describe the factors influencing the PK of a molecule and establish new dose regimens optimised for a given population (in this case an ICU population) using Monte Carlo simulations, has never been developed for ceftobiprole given by continuous infusion.

The ultimate aim of so-called adequate antibiotic therapy is to obtain the right therapeutic concentrations at the infection site. During a pulmonary infection, the targeted concentrations of antibiotics in the alveolar liquid must be above the minimal inhibitory concentration value at the end of the dose interval for so-called " time-dependent " antibiotics like cephalosporins. Obtaining these efficient concentrations is often made difficult by the beta-lactams' mediocre pulmonary diffusion and can require an increase in doses in order to reach the PK/PD target at the infection site and/or the use of continuous administration of beta-lactamines. Indeed, this way of administrating is being privileged more and more in order to optimise the time spent above the minimal inhibitory concentration.

This pharmacokinetic study is the first to be carried out among a population of ICU patients and one that focuses on pulmonary diffusion of ceftobiprole for the treatment of severe CAP. The main benefits expected are to determine the most suitable doses of ceftobiprole when this molecule is used to treat ICU patients suffering from CAP. With the help of this population analysis, the main aim of the study is therefore to describe the pharmacokinetics (PK) of the plasma and pulmonary diffusion of ceftobiprole administered at high-dosage (500 mg loading dose followed by 2.5 g under continuous infusion for 24h) for severe community-acquired pneumonia under mechanical ventilation.

The secondary aims are :

A- Determine whether the pharmacokinetic / pharmacodynamic (PK/PD) targets can be achieved in the plasma and epithelial lining fluid with the recommended doses of ceftobiprole.

B- Define the optimal dose regimen for ceftobiprole in this population. C- Evaluate the clinical recovery (at Day 3 and Day 8) and microbiological recovery (at Day 3).

D- Evaluate the clinical evolution. E- Evaluate the clinical and biological tolerance.

Eligibility criteria: Inclusion Criteria:

* All patients (or his/her representative for those patients who are unable to express their consent) who have given free, informed consent, and signed the consent form.
* All patients affiliated to or benefitting from a health insurance scheme.
* All patients hospitalised in the intensive care unit with severe acute community-acquired pneumonia requiring the use of mechanical ventilation: this is characterised by signs and symptoms corresponding to an infection of the lower respiratory tract and imaging data corresponding to bacterial pneumonia.The patient has been under mechanical ventilation for less than 24 hours.

Exclusion Criteria:

* Any patient who is already taking part in another interventional study that may influence the main criterion for judgement.
* Any patient who is in the exclusion period determined by another study.
* Any patient under curatorship or guardianship established by a court
* Any patient who is pregnant, about to give birth or breastfeeding.
* Any patient with a contra-indication or allergy to beta-lactams
* Any patient whose survival is estimated at less than 48 hours
* Any patient whose discharge from hospital is planned for 24 hours after admission
* Any patient whose creatinine clearance is estimated at less than 50 ml/min or who is undergoing renal replacement therapy
* Any patient undergoing extracorporeal life support.

Primary outcomes:
measure: Plasma concentration of ceftobiprole on Day 1
timeFrame: Day 1
measure: Blood test after injection of loading-dose Ceftobiprole (Cmax) for 30 minutes
timeFrame: Day 1 (after the 30-minute injection)
measure: Blood test 2 hours AFTER beginning antibiotic therapy with ceftobiprole
timeFrame: Day 1, 2 hours from start of treatment
measure: Blood test 6 hours AFTER beginning antibiotic therapy with ceftobiprole
timeFrame: Day 1, 6 hours from start of treatment
measure: Blood test 8 hours AFTER beginning antibiotic therapy with ceftobiprole
timeFrame: Day 1, 8 hours from start of treatment
measure: Blood test 12 hours AFTER beginning antibiotic therapy with ceftobiprole
timeFrame: Day 1, 12 hours from start of treatment
measure: Time 2 blood test on third day of antibiotic therapy with ceftobiprole
timeFrame: Day 3 at Time 2
measure: Time 6 blood test on third day of antibiotic therapy with ceftobiprole
timeFrame: Day 3 at Time 6
measure: Time 8 blood test on third day of antibiotic therapy with ceftobiprole
timeFrame: Day 3 at Time 8
measure: Time 12 blood test on third day of antibiotic therapy with ceftobiprole
timeFrame: Day 3 at Time 12
Secondary outcomes:
measure: Pulmonary concentration of ceftobiprole on Day 3
timeFrame: On Day 3 of treatment with ceftobiprole
measure: Plasma concentration BEFORE treatment
timeFrame: Day 1
measure: Plasma concentration AFTER maximum dose of ceftobiprole on Day 1
timeFrame: Day 1
measure: Plasma concentration after two hours at the steady-state
timeFrame: Day 1
measure: Plasma concentration after 6 hours at the steady-state
timeFrame: Day 1
measure: Plasma concentration after 8 hours at the steady-state
timeFrame: Day 1
measure: Plasma concentration after 12 hours at the steady-state
timeFrame: Day 1
measure: Plasma concentration at Time 2 on Day 2 of the steady-state
timeFrame: Day 2 at Time 2
measure: Plasma concentration at Time 6 on Day 2 of the steady-state
timeFrame: Day 2 at Time 6
measure: Plasma concentration at Time 8 on Day 2 of the steady-state
timeFrame: Day 2 at Time 8
measure: Plasma concentration at Time 12 on Day 2 of the steady-state
timeFrame: Day 2 at Time 12
measure: Plasma concentration on Day 3 (after end of 24H infusion with ceftobiprole)
timeFrame: Day 3 at Time 2
measure: Plasma concentration on Day 3 (after end of 24H infusion with ceftobiprole)
timeFrame: Day 3 at Time 6
measure: Plasma concentration on Day 3 (after end of 24H infusion with ceftobiprole)
timeFrame: Day 3 at Time 8
measure: Plasma concentration on Day 3 (after end of 24H infusion with ceftobiprole)
timeFrame: Day 3 at Time 12
measure: Presence or not of Ceftobiprole in the epithelial lining fluid on Day 3 (after end of 24H infusion with ceftobiprole)
timeFrame: Day 3
measure: Dose regimens defined by Monte Carlo simulations
timeFrame: After day 3
measure: Test of cure on Day 3
timeFrame: Day 3
measure: Test of cure on Day 8
timeFrame: Day 8
measure: Test of microbiological cure on Day 3
timeFrame: Day 3
measure: Duration of stay at the intensive care unit.
timeFrame: Day 28
measure: Vital status
timeFrame: Day 28
measure: Number of days alive without mechanical ventilation
timeFrame: Day 28
measure: Renal function on Day 1
timeFrame: Day 1
measure: Renal function on Day 2
timeFrame: Day 2
measure: Evaluation of renal function on Day 3
timeFrame: Day 3
measure: Evaluation of renal function on Day 8
timeFrame: Day 8
measure: Evaluation of liver function on Day 1
timeFrame: Day 1
measure: Evaluation of liver function on Day 2
timeFrame: Day 2
measure: Evaluation of liver function on Day 3
timeFrame: Day 3
measure: Evaluation of liver function on Day 8
timeFrame: Day 8
Other outcomes:
Locations:
city: Pierre Bénite
country: France
facility: Centre Hospitalier Lyon Sud,
state: Auvergne-Rhône-Alpes
city: Nîmes
country: France
facility: CHU de Nîmes
state: Gard
Study officials:
References: