Determination of tobramycin serum concentrations in ICU patients treated with SDD: a prospective study.

Selective decontamination of the digestive tract (SDD) has as main objective to
reduce the risk of nosocomial pneumonia and candidaemie. In addition, an
increase in antibiotic resistance is prevented by reducing the use of
antibiotics for these infections. By eliminating aerobic potentially pathogenic
micro-organisms (PPM), and yeasts from the gastrointestinal tract and
oropharnyx the pharynx becomes no longer colonized with PPM and the risk of a
nosocomial pneumonia caused by micro-aspiration is dereased. By early
elimination of yeast in the digestive tract a general colonization (respiratory
tract, wounds, urinary tract) is contested and thus decreases the risk of
candidaemie. Within the Martini hospital all the patients admitted to the ICU
and Medium Care ICU with an expected duration of> 72 hours and / or expected
duration of ventilation for> 48 hours will get treatment with SDD.

The SDD protocol consists of a combination of colistin / polymyxin E,
tobramycin, and amphotericin B which is applied in the oral cavity in
ventilated patients in a 2% concentration in Orabase paste, and is applied in
the gastrointestinal tract by means of a suspension with the same antibiotics
via the gastric tube. In patients that are not ventilated the mouth is rinsed
with the suspension and then swallowed. This decontaminates the entire
digestive tract (if intact). Furthermore, a short intravenous antibiotic
therapy is given during the first four days, in order to treat or prevent
emerging primary endogenous infections. The short intravenous antibiotic
treatment is given only if there aren't any other antibiotics already given for
other reasons.

It is stated that tobramycin is not absorbed after oral administration, making
systemic tobramycin serum concentrations not expected. Detectable tobramycin
serum concentrations (> 0.05 mg / L), however, have been reported in patients
receiving SDD and are related to a decreased intestinal barrier in sepsis,
shock or after major abdominal surgery. Renal impairment is associated with
decreased systemic clearance of tobramycin and can thus lead to persistent high
serum concentrations and / or accumulation of systemic tobramycin. To date,
there is in the Martini Hospital currently no policy with regard to the
determination of serum tobramycin concentrations in patients with an increased
risk of systemic absorption of tobramycin. Determination of serum tobramycin
concentration only occurs in patients with an increased risk of reduced
elimination of tobramycin, so patients undergoing CVVH, who are
(intermittently) dialyzed or have a eGFR <30 ml / min (in accordance with SWAB
directive). There is also in the Martini hospital (rural) no clear policy on
how to proceed with proven high tobramycin serum concentrations.

Recently, we have found high serum tobramycin concentrations (> 2 mg / L) in an
ICU patient treated with SDD . Because this patient was not treated with
systemic tobramycin it can be concluded that there has been absorption of
tobramycin from the SDD. This patient had several risk factors for increased
absorption and decreased elimination of tobramycin. The persistent SIRS,
sepsis, renal dysfunction, major abdominal surgery and multiple administration
routes of SDD (mouth paste, suspension and suppository) may have all
contributed to the high systemic tobramycin serum concentrations.

From the systemic useof tobramycin it is known that the height of the trough
serum concentration is a measure for the probability of the occurrence of
nephrotoxicity. In the SWAB TDM monograph tobramycin, which is focused on IV
administration of tobramycin, it is stated that when a trough serum
concentration higher than 2 mg / L, tobramycin dosage should be adjusted. At a
serum tobramycin concentration between 1 and 2 mg / L dose optimization is
possibly necessary. So it is plausible that patients who have high tobramycin
serum concentrations (> 2 mg / L) due to SDD, have an increased risk for the
occurrence of nephrotoxicity and ototoxicity.

The purpose of this study is to provide insight in to what extent clinically
significant systemic absorption of tobramycin occurs (resulting in a serum
tobramycin concentration> 1.0 mg / L) in ICU and Medium Care ICU patients who
are being treated with the SDD.
In addition, the goal of this research is to gain insight into risk factors
that may contribute to an increased risk of absorption of tobramycin in the use
of SDD.

The study is an observational cohort study. The cohort consists of all ICU
patients and Medium Care ICU patients treated between February 1, 2016 and
december 31, 2016 with SDD. In this group of patients a serum tobramycin
concentration will be determined up to four times, using a immunoassay from
Roche, the method of analysis which is currently being used for this. This
serum is obtained by taking an additional tube of blood from the artery line,
during the standard blood collection round at 6.00 am.

Withdrawal of blood from the artery line is an act that is performed several
times daily in the ICU. It's standard procedure that each patient gets an
artery at admission to the ICU because the ICU patient is by definition a
critically ill patient. The IC staff is very competent in carrying out such
actions. Therefore, there are no additional risks associated with this
research.
The burden for patients is low, since blood will be collected not more than
four times from an artery line for the purpose of this investigation. At
admission at the ICU each patient standardly gets an artery line (= medical
policy) and also, blood is taken from every IC patient daily at 6:00 am. In
this study only once a week an extra tube of blood is drawn from the already
existing artery. The patient does not need an extra injection for this study.
High tobramycin serum concentrations increase a risk for renal dysfunction
among other things. It is important, therefore, that high serum tobramycin
concentrations are detected at an early stage. The results from this study are
therefore important for future medical practice. For the reason above, this
research is justified in the light of burdens and / or risks for the patients.