Objectives The primary objective of the study is to determine the pharmacokinetics of
beta-lactam antibiotics in patients with infectious endocarditis, and how the
pharmacokinetic profile is associated with various patient factors (e.g. age, body
weight, renal function). Secondary objectives are to descriptively assess potential
associations between drug exposure, pharmacokinetic/pharmacodynamic targets and clinical
outcomes.
Inclusion of patients and sample size Patients are prospectively included at the
departments of infectious diseases, internal and acute medicine, cardiology and thoracic
surgery at four University Hospitals in Sweden; Uppsala University Hospital, Sahlgrenska
University Hospital in Gothenburg, Skåne University Hospital in Lund and Karolinska
University Hospital in Stockholm. Potential participants are screened for using the
electronic medical records. Inclusion criteria are as follows: (1) admission at one of
the study wards, (2) a diagnosis of probable or verified infectious endocarditis, (3)
treatment with ampicillin, penicillin G, cefotaxime or cloxacillin and (4) informed
written consent to participate in the study. The following exclusion criteria will be
applied: (1) age less than 18 years and (2) ongoing or planned hemodialysis.
Based on previous research using similar methods, 30 patients per antibiotic substance
(total 150 patients) is considered sufficient to develop a robust mathematical model.
Collection of blood samples and patient data Following inclusion, a series of samples
will be taken within one week from start of treatment. Beta-lactams are normally
prescribed at 6-8 h dose intervals. One series of 6 blood samples will be collected at 0,
0,5, 1, 2, 4 and 6 or 8 h (depending on dose interval, prior to next dose) after
administration of antibiotics. Thereafter, samples will be collected once weekly and 0, 3
or 4 (mid-dose interval) and 6 or 8 h (depending on dose interval, prior to next dose).
Information on patient characteristics, including age, body weight, and gender, will be
obtained from the electronic medical records. Further, the results of biomarkers (e.g.
albumin, creatinine, CRP), collected as part of routine practice, will be noted. If not
collected as standard of care, patients will be subject to extra samples to ensure
biomarkers are monitored at least twice weekly.
Clinical outcomes Treatment failure is defined as mortality during antibiotic treatment
for infectious endocarditis or relapse of endocarditis within 6 months after completion
of therapy with isolation of the same pathogens as in the initial episode. Other
indicators of treatment failure include acute surgery for endocarditis, clinical
deterioration resulting in transfer to the ICU, thromboembolic events more than 7 days
after initiation of antibiotics and resistance development of the causative bacteria. The
following side effects will be monitored: deterioration of renal impairment, allergic
reaction suspected to be caused by the antibiotic treatment, Clostridioides difficile
enteritis or other suspected side effects resulting in a shift of therapy to another
antibiotic.
Handling of samples and data Blood samples will be stored at -70 degrees Celsius at the
Department of infectious diseases at the respective hospital where the samples have been
collected. The samples will be sent to Sahlgrenska University Hospital, Gothenburg, for
determination of drug concentrations.
Patient names and personal identification numbers will be replaced by a number. Personal
data will be stored at the Department of infectious diseases at the respective hospital
where the patient has been included. Only the responsible researchers will have access to
the code key and be able to link personal information to the individual participants. All
information will be handled in accordance with the General Data Protection Regulation
(GDPR) and all analyses and presentation of data will be performed using anonymous data.
Mathematical modeling and simulations The collected drug concentrations will be analyzed
by non-linear mixed effects modeling using NONMEM. Associations between administered dose
and the measured drug concentration over time will be described (pharmacokinetics).
Correlations with patient characteristics and biomarkers, as well as clinical outcomes in
terms of cure, mortality and documented side effects (pharmacodynamics) will be explored.