Dose IndividualizAtion of Beta-lactam and fluOroquinoLone AntiBiotics in ICU patients: to TDM or not to TDM and the effects on Outcome (DIABOLO-study)

INTERVENTION: Trade Name: Cefotaxim 500mg, 1000mg Pharmaceutical Form: Powder for solution for injection Trade Name: Ceftazidim 500mg, 1000mg, 2000mg Pharmaceutical Form: Powder for solution for injection Trade Name: Ceftriaxon 1000mg, 2000mg Pharmaceutical Form: Powder for solution for injection Trade Name: Cefuroxim 750mg, 1500mg Pharmaceutical Form: Powder for solution for injection Trade Name: Amoxicillin 125mg, 250mg, 500mg, 1g Pharmaceutical Form: Powder for solution for injection Trade Name: Amoxicillin/Clavulanic acid 500mg/50mg,1000mg/200mg, 2000 mg/200 Pharmaceutical Form: Powder for solution for injection Trade Name: Flucloxacillin 250mg, 500mg, 1g Pharmaceutical Form: Powder for solution for injection Trade Name: Natrium‐penicilline G 1.000.000IE, 10.000.000IE Pharmaceutical Form: Powder for solution for injection Trade Name: Piperacillin/tazobactam 2/0,25g, 4/0,5g Pharmaceutical Form: Powder for solution for injection Trade Name: Meropenem 500mg, 1g Pharmaceutical Form: Powder for solution for injection Trade Name: Ciprofloxacine 100mg/50ml, 200mg/100ml, 400mg/200ml Pharmaceutical Form: Solution for injection CONDITION: ICU patients with infection Therapeutic area: Diseases [C] ‐ Bacterial Infections and Mycoses [C01] PRIMARY OUTCOME: Main Objective: The aim of this trial is to evaluate a new early dosage adjustment strategy (TDM) of beta‐lactam and fluoroquinolones in adult ICU patients to achieve the adequate pharmacodynamic targets (PDT), compared to the usual treatment strategy. Primary end point(s): Attainment of drug levels will be calculated using the PDT. PDT indices are calculated for each individual patient. The treatment drug MICECOFF and the free (unbound = ƒ) drug exposure value are used to calculate the following PK/PD indices: ; •Beta‐lactam: %ƒT>MICECOFF (including % of patients with 100%ƒT>MICECOFF in both groups).; This means that patients need an unbound beta‐lactam serum concentration of 100% above the MIC during a dosing interval. ; •Fluoroquinolone: ƒAUC/MICECOFF (including % of patients with ƒAUC/MICECOFF=100 in both groups); This means that patients need an unbound area under the curve concentration equals or above 100/MIC ratio during the dosing interval. ; The area under the curve (mathematically known as definite integral) in a plot of concentration of drug in blood plasma against time. ; Secondary Objective: Secondary aims are clinical outcome, the impact on antimicrobial resistance, and cost‐effectiveness analyses between the TDM and non‐TDM group. Timepoint(s) of evaluation of this end point: 24‐months SECONDARY OUTCOME: Secondary end point(s): The secondary aims are to compare TDM‐tailored group with the usual treatment strategy with respect to 1) the proportion of subjects with serum concentration within the concentration targets, and 2) the clinical (e.g. in terms of fever), biological (e.g. in terms of CRP) and bacteriological (e.g. in terms of blood culture) efficacy of this early dosage adjustment strategy of beta‐lactam and fluoroquinolone antibiotics. ; Furthermore, the impact on antimicrobial resistance (AMR) will be measured by taking samples from the presumptive infection, using culture techniques and quantitative PCR (qPCR). This technique was recently described for carbapenemases and in our own research group for ESBLs. Subsequently, the results will be plotted as a function of ƒT>MIC and ƒAUC/MIC to determine specific patterns. The advantage of this approach is that even if there is no significant difference between the groups, it may still provide a distinctive pattern over the whole study group. ; Timepoint(s) of evaluation of this end point: 24‐months In order to be eligible to participate in this study, a subject must also meet all of the following criteria: INCLUSION CRITERIA: All patients admitted to the ICU and given standard of care intravenous therapy of either one or both of the target antibiotic classes are included. Antibiotic initiation based on clinical suspicion of infection and/or cultured pathogens susceptible to the target drugs, initial dosage prescription, and duration of therapy are at the discretion of the attending physician. •=18 years of age •Receiving intravenous antibiotic therapy of the target drugs •Treatment should be aimed for at least 2 days. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 100 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 150