Little is known of beta-lactam antibiotics' true therapeutic plasma concentration range. The aims of this study are to define evidence-based, safe and effective upper and lower limits of the plasma concentrations of imipenem, meropenem, amoxicillin, flucloxacillin, piperacillin, ceftazidime and cefepime in patients at increased risk of serious bacterial infections and currently understudied pharmacokinetics (the critically ill, the elderly, and the immunosuppressed). This prospective observational study will include adult patients with suspected or confirmed systemic bacterial infection receiving one of the above-named antibiotics and hospitalized in intensive-care, step-down, or hematology-oncology units of the Geneva University Hospitals (HUG). Eligible patients will be identified via the electronic health record (EHR). Patients receiving traditional intermittent dosing or prolonged infusions will undergo TDM for at least one intermediate (mid-interval) and one trough level at 24 hours (-12 or +48 hours) after the therapy's start. Patients receiving continuous infusions will undergo TDM for at least one steady-state level. Clinical course will be observed for 30 days from the start of the study antibiotic (1st day of study antibiotic =day 1). The primary outcome is incidence of clinical toxicity through day 30 after start of study antibiotic (as stratified by BL trough concentration). Secondary outcomes are listed below.
Little is known of beta-lactam antibiotics' true therapeutic plasma concentration range. The aims of this study are to define evidence-based, safe and effective upper and lower limits of the plasma concentrations of imipenem, meropenem, amoxicillin, flucloxacillin, piperacillin, ceftazidime and cefepime in patients at increased risk of serious bacterial infections and currently understudied pharmacokinetics (the critically ill, the elderly, and the immunosuppressed). This prospective observational study will include adult patients with suspected or confirmed systemic bacterial infection receiving one of the above-named antibiotics and hospitalized in intensive-care, step-down, or hematology-oncology units of the Geneva University Hospitals (HUG). Eligible patients will be identified via the electronic health record (EHR). Patients receiving traditional intermittent dosing or prolonged infusions will undergo TDM for at least one intermediate (mid-interval) and one trough level at 24 hours (-12 or +48 hours) after the therapy's start. Patients receiving continuous infusions will undergo TDM for at least one steady-state level. Clinical course will be observed for 30 days from the start of the study antibiotic (1st day of study antibiotic =day 1). The primary outcome is incidence of clinical toxicity through day 30 after start of study antibiotic (as stratified by BL trough concentration). Secondary outcomes are listed below.
Study Type
OBSERVATIONAL
Enrollment
771
The study is observational.
Geneva University Hospitals
Geneva, Canton of Geneva, Switzerland
Incidence of clinical toxicity through day 30 after start of study antibiotic
Incidence of clinical toxicity through day 30 after start of study antibiotic (as stratified by BL trough concentration)
Time frame: day 30 after start of antibiotic
Clinical response: incidence of clinical cure
Clinical response to therapy through day 30 will be measured study-wide. "Clinical response" is either clinical cure (resolution of symptoms) or clinical failure (lack of improvement in signs and symptoms of infection OR recurrence of signs/symptoms of infection after initial improvement OR death in the 30-day study period considered at least possibly due to the infection). Where the MIC is unavailable, EUCAST epidemiologic cutoffs (ECOFF) will be used; if no organism is isolated, non-species-related breakpoints for targeted organisms (e.g., Pseudomonas aeruginosa) will be used.
Time frame: day 30
clinical response in patients with neutropenic fever: incidence of clinical cure in this subpopulation
Clinical response (as in outcome no. 2) in the subgroup of patients with neutropenic fever at the time of BL therapy. ("Clinical response" is either clinical cure (resolution of symptoms) or clinical failure (lack of improvement in signs and symptoms of infection OR recurrence of signs/symptoms of infection after initial improvement OR death in the 30-day study period considered at least possibly due to the infection).)
Time frame: day 30
30-day mortality attributable to the treated infection
30-day mortality attributable to the treated infection
Time frame: day 30
30-day all-cause mortality
30-day all-cause mortality
Time frame: day 30
incidence of reversible toxicity
Proportion of adverse events (AE) that are reversible after discontinuation of the relevant BL antibiotic
Time frame: day 30
Incidence of Clostridium difficile infection
Incidence of Clostridium difficile infection
Time frame: day 30
Incidence of clinical toxicity of piperacillin-tazobactam when co-administered with vancomycin
Incidence of clinical toxicity of piperacillin-tazobactam (and other beta-lactam antibiotics) when co-administered with vancomycin
Time frame: day 30
Incidence of emergence of resistance
Prevalence of emerging resistance to study antibiotics in clinical isolates (from baseline)
Time frame: day 30
Incidence of undetectable beta-lactam plasma concentrations
Proportion of patients with undetectable beta-lactam trough and/or intermediate concentrations
Time frame: day 30
Incidence of off-label prescribing
Proportion of patients for whom (a) beta-lactam dosing is "off-label" according to Swiss recommendations and (b) there are no dosing recommendations (e.g., hemofiltration)
Time frame: day 30
The correlation of free versus total flucloxacillin concentrations
The correlation of free versus total flucloxacillin concentrations (in a subset of patients, free flucloxacillin plasma levels will also be measured and compared to those of total flucloxacillin).
Time frame: day 30
Median intermediate and trough plasma concentrations of tazobactam
In a subset of patients receiving piperacillin/tazobactam, median intermediate and trough plasma concentrations of tazobactam (beta-lactamase inhibitor) in proportion to piperacillin in patients receiving piperacillin-tazobactam
Time frame: through day 30
Beta-lactam trough concentration/minimal inhibitory concentration (MIC) index
The trough beta-lactam (BL) concentration/minimal inhibitory concentration (MIC) index on day 1 (±1) will be measured in all patients for later correlation analyses with clinical outcomes (clinical success versus failure).
Time frame: day 1 (±1)
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