Clinical trial NCT04070469: Plasma Concentrations of Amoxicillin Administered in High-doses During the First Week of Treatment (MAX-AMOX)
Official title: Plasma Concentrations of Amoxicillin Administered in High-doses During the First Week of Treatment : Intra- and Inter-individual Variability, Factors Associated With Overdose and Adverse Events
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Infection, Bacterial
Keywords: amoxycillin
drug kinetics
drug toxicity
crystalluria
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2019-08-28
Enrollment: 142
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: Amoxicillin is the most prescribed antibiotic in France. High dose intravenous amoxicillin, (dosage greater than or equal to 150 mg / kg / day or 12 g per day for patients over 80 kg) is used in the treatment, in particular, of infectious streptococcal endocarditis. oral, streptococci gallolyticus and enterococci, infections of the central nervous system with sensitive germs including Streptococcus pneumoniae and Listeria monocytogenes, osteo articular infections. The dose-related adverse effects of this antibiotic are nephrological (crystalluria may lead to acute renal failure) and neurologic. Recently, the number of amoxicillin crystalluria reported to pharmacovigilance centers has increased, having led the National Agency of drug and health products safety (ANSM) to recommend the determination of the residual level of amoxicillin during the first week of treatment of these patients. Nevertheless, there is no precise therapeutic target in patients treated with high dose amoxicillin except in the context of critical care. The authors suggest the interest of a target between 4 and 10 times the minimum inhibitory concentration (MIC) based on in vitro efficacy studies, and retrospective observations of toxicity cases.

Detailed description: Patients will be followed for 8 days. After inclusion, (day of the introduction of high-dose amoxicillin treatment), the residual amoxicillin plasma concentrations will be determined at Day1, Day4 +/- 1 day and Day7 +/- 1 day of the start of treatment. A urine collection will be performed the same day to search for crystalluria and measure the pH and urinary density.

In case of KDIGO (Kidney Disease Improving Global Outcomes) 2 or 3 stage renal failure or neurological signs compatible with overdose, residual amoxicillin and crystalluria and urinary density and urinary pH will be measured during the day of discovery of renal failure.

In the case of KDIGO stage 1 kidney failure, a residual level of amoxicillin and a crystalluria search and the measurement of urinary density and urinary pH will be carried out the following day, when serum creatinine is checked according to usual practices.

At day 7 the clinical and infectious biological evolution of the patient will be collected.

Eligibility criteria: Inclusion Criteria:

* Major patient, male or female, who has a bacterial infection requiring high dose intravenous amoxicillin antibiotic therapy (greater than or equal to 150 mg / kg / day with a maximum of 12 grams per day or 12 grams per day for patients over 80 kg), according to ANSM recommendations.
* Able to provide informed consent to participate.
* Covered by a Social Security scheme.

Exclusion Criteria:

* Pregnant, breastfeeding, or likely to be pregnant women and in the absence of a negative pregnancy test (blood HCG beta).
* Patients under guardianship, curatorship, deprived of liberties or subject to a safeguard of justice.
* Septic shock justifying treatment with pressurized amines.
* Patient under ventilatory or circulatory support.
* Patients on dialysis at Baseline or with a creatinin clearance less than or equal to 30mL / min
* Refusal of participation
* Hypersensitivity to the active substance, to penicillins. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam (e.g. cephalosporin, carbapenem or monobactam)

Primary outcomes:
measure: Residual plasma concentrations of administered in high doses amoxicillin
timeFrame: Day 7
measure: Residual plasma concentrations of administered in high doses amoxicillin
timeFrame: Day 4
measure: Residual plasma concentrations of administered in high doses amoxicillin
timeFrame: Day 1
Secondary outcomes:
measure: search for cystalluria, description of crystals, and infrared spectropscopy to determine crystals composition
timeFrame: Day 7
measure: search for cystalluria, description of crystals, and infrared spectropscopy to determine crystals composition
timeFrame: Day 4
measure: search for cystalluria, description of crystals, and infrared spectropscopy to determine crystals composition
timeFrame: Day 1
measure: proportion of residual plasma concentrations above 10 minimal inhibitory concentration (MIC)
timeFrame: day 7
measure: proportion of residual plasma concentrations above 10 minimal inhibitory concentration (MIC)
timeFrame: day 4
measure: proportion of residual plasma concentrations above 10 minimal inhibitory concentration (MIC)
timeFrame: day 1
measure: density of urines in g/mL
timeFrame: Day 7
measure: pH of urines
timeFrame: Day 7
measure: density of urines in g/mL
timeFrame: Day 4
measure: pH of urines
timeFrame: Day 4
measure: density of urines in g/mL
timeFrame: Day 1
measure: pH of urines
timeFrame: Day 1
measure: confusional state
timeFrame: Day 1
measure: confusional state
timeFrame: Day 4
measure: confusional state
timeFrame: Day 7
measure: encephalitic signs
timeFrame: Day 1
measure: encephalitic signs
timeFrame: Day 4
measure: encephalitic signs
timeFrame: Day 7
measure: epilepsy
timeFrame: Day 1
measure: epilepsy
timeFrame: Day 4
measure: epilepsy
timeFrame: Day 7
measure: age associated with evolution of amoxicillin plasma concentrations
timeFrame: Day 0
measure: body mass index associated with evolution of amoxicillin plasma concentrations
timeFrame: Day 0
measure: renal function at treatment initiation associated with evolution of amoxicillin plasma concentrations
timeFrame: Day 0
measure: renal function impairment during treatment
timeFrame: Day 1
measure: renal function impairment during treatment
timeFrame: Day 4
measure: renal function impairment during treatment
timeFrame: Day 7
measure: germ involved
timeFrame: Day 0
measure: MIC of germ
timeFrame: Day 0
measure: site of infection
timeFrame: Day 0
Other outcomes:
Locations:
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Magali VIDAL
role: PRINCIPAL_INVESTIGATOR
References: