Right Dose, Right Now: Randomized Controlled Clinical Trial

Sepsis is a major and growing problem. In the Netherlands alone, around 15.000
patients are diagnosed with severe sepsis each year. Despite major scientific
efforts, including many failed clinical trials mainly focusing on inflammatory
mediators and the introduction of care bundles, the mortality rate for severe
sepsis still remains unacceptably high at around 30%. This is alarming,
especially since the incidence of sepsis continues to increase and now exceeds
that of colon cancer, breast cancer and AIDS combined.

Antibiotics are essential for treating sepsis. Their early and appropriate use
has repetitively been shown to reduce mortality rates. However, achieving
adequate antibiotic exposure in critically ill patients is a major challenge
due to markedly different pharmacokinetic (PK) profiles in the critically ill.
Nevertheless, doctors still rely on standard antibiotic dosing schemes, that
were developed based on data from healthy volunteers and non-critically ill
patients. Depending on patient characteristics, clinical course and therapy,
this strategy may result in underdosing and/or drug-related toxicity during the
course of intensive care treatment.

Therefore, we developed AutoKinetics (AutoK) software. AutoK aims to make use
of patient data that is available from the electronic patient records, for
example about fluid balance and renal function. Using this data, AutoK is able
to give fast and precise dosing advice, using published pharmacokinetic models
of any drug. AutoK runs on the computer at the bedside. Thus, advice is readily
available, even before treatment is started, and is continuously updated as
disease and therapy evolve: true personalized dosing.

We hypothesize that AutoK can improve antibiotic dosing, morbidity and
mortality for severe sepsis.

To assess the influence of dosing guided by AutoK on achieving PK targets and
clinical endpoints in intensive care patients with sepsis.

Multicenter, randomized controlled, two-arm, parallel-group, superiority trial

Patients will be randomized to one of two groups.

Group 1 (Control group): standard intravenous antibiotic therapy based on
current clinical guidelines and practice. Standard therapy will include TDM for
vancomycin, but not for the beta-lactams and ciprofloxacin. The standard
antibiotic dosing schemes are:

o OLVG:
* Vancomycin: continuous infusion 1000 mg/24h
* Ciprofloxacin: 2 x 400mg
* Cefotaxim: 4 x 1000mg
* Meropenem: 3 x 1000mg

o VUmc:
* Vancomycin: 1 x 1000 mg
* Ciprofloxacin: 3 x 400 mg
* Ceftriaxon: 1 x 2000 mg
* Meropenem: 3 x 1000 mg

Local standard protocols allow for higher dosing in case of suspicion of
atypical pneumonia, central nervous system infection or endocarditis.

Group 2 (Experimental group): Personalized antibiotics dosing guided by AutoK,
based on PK models combined with patient data from the electronic patient
record.

Possible benefits to the subject include improved clinical outcome as a result
of improved antibiotic dosing. Further, if feasible and successful,
individualized antibiotic dosing could be a major step forward in the treatment
of sepsis, which is a significant source of worldwide morbidity and mortality.

Estimated risks are small given AutoK*s safety profile, dose warnings and
mandatory dose verification by the treating physician, as explained in the
investigational medical device dossier. Burden is limited to extra blood
sampling from an existing line (6-10 samples of 4 ml per antibiotic) and
participation in follow-up questionnaires.

We therefore believe that the benefits outweigh the risks and burden.