This study evaluates the administration of beta-lactam antibiotics in extended infusion in hematological patients with febrile neutropenia after 5 days of treatment. The beta-lactam antibiotics analyzed are the following: piperacillin-tazobactam, cefepime and meropenem. Half of patients will receive the antibiotic in intermittent infusion, while the other half will receive it in extended infusion.
Febrile neutropenia (FN) is a very frequent complication in patients with hematological malignancies. It is associated with an important morbidity and mortality. Nowadays the use of betalactam antibiotics (BLA) in extended or continuous infusion (EI, CI) instead of intermittent infusion (II), has demonstrated a therapeutic success and lower mortality rate in critically ill intensive care patients. Neutropenic patients are a particular population since FN is assoicated with pathophysiological variations that compromise pharmacokinetic parameters of BLA, and may therefore, diminish their clinical efficacy. Information regarding the usefulness of BLA in EI in neutropenic hematologic patients is scarce. The objective of this randomized clinical trial is to demonstrate the clinical superiority of the administration of BLA in EI compared to II in patients with FN.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
150
Patients with FN who empirical treatment with piperacillin-tazobactam 4g/6h
Patients with FN who required empirical treatment with cefepime 2g/8h
Patients with FN who required empirical treatment with meropenem 1g/8h
Hospital Duran i Reynals
L'Hospitalet de Llobregat, Barcelona, Spain
RECRUITINGClinical efficacy of extended infusion: Number of patients with defervescence
Number of patients with defervescence (\<37.5 ºC, for 24 hours) without modifying the antibiotic treatment
Time frame: 5 days
Pharmacokinetic target
Number of patients in whom the free antibiotic concentration remains above the MIC of the suspected or isolated microorganism, for 50%, 75% and 100% of the dosing interval.
Time frame: 5 days
Inflammatory biomarker
Number of patients who normalize or decrease in more than 50% of the peak value of the C-reactive protein.
Time frame: 5 days
Overall mortality at 30 days
Number of patients who died for any reason
Time frame: 30 days
Bacteraemia clearance
Time in days until bacteraemia clearance.
Time frame: 30 days
Adverse events
Incidence of adverse events in both groups
Time frame: 30 days
Pharmacokinetic analysis and population pharmacokinetics of meropenem, piperacillin and cefepime in neutropenic patients: Volume of distribution
Population mean value of volume of distribution of antibiotics during critical illness. Mean population volume of distribution will be derived from pooled data of antibiotic concentrations. Covariates of influence on volume of distribution will be incorporated within a population pharmacokinetic model.
Time frame: 5 days
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Pharmacokinetic analysis and population pharmacokinetics of meropenem, piperacillin and cefepime in neutropenic patients: Clearance
Population mean value of clearance of antibiotics during critical illness. Mean population clearance will be derived from pooled data of antibiotic concentrations. Covariates of influence on drug clearance will be incorporated within a population pharmacokinetic model
Time frame: 5 days
Covariables analysis: biometric values: weight
Assessment of the impact of patient's weight \[in kg\]
Time frame: 5 days
Covariables analysis: biometric values: age
Assessment of the impact of patient's age \[in years\]
Time frame: 5 days
Covariables analysis: biochemical data: serum albumin
Assessment of the impact of total serum albumin \[in g/L\]
Time frame: 5 days
Covariables analysis: biochemical data: blood urea
Assessment of the impact of the urea \[in mmol/L\]
Time frame: 5 days
Covariables analysis: biochemical data: blood creatinine
Assessment of the impact of the creatinine \[in umol/L\]
Time frame: 5 days
Covariables analysis: clinical data: 24h diuresis
Assessment of the impact of 24h diuresis \[in mL/day\]
Time frame: 5 days
Pharmacokinetic analysis and population pharmacokinetics: time above a critical concentration value for plasma concentrations
Analysis of the antibiotic pharmacokinetic profiles by means of appropriate software to calculate the actual mean and median values of the fraction of the time between two successive drug administrations during which plasma concentrations of meropenem, piperacillin and cefepime remain above a critical value ("S" breakpoint of the corresponding antibiotic \[meropenem, piperacillin and cefepime: European Committee for Antimicrobials Susceptibility Testing \[EUCAST\] value) in the study population, and to determine its value in a simulated population (Monte Carlo simulations; 1000 simulated patients).
Time frame: 5 days