Development of a project for interprofessional collaboration between medical and pharmacy students to improve medication safety in polypharmacy (PILLE).

Aim: Interprofessional collaboration is particularly relevant to patient safety in outpatient care with polypharmacy. The educational project "PILLE" is meant to give medical and pharmacy students an understanding of the roles and competencies needed for cooperation in the provision of healthcare and to enable interprofessional learning. Method: The curriculum is aimed at pharmacy and medical students and was developed in six steps according to the Kern cycle. It is comprised of an interprofessional seminar, a joint practical training in a simulated pharmacy, and a tandem job shadowing at a primary care practice. The project was implemented in three stages due to the pandemic: The interprofessional online seminar based on the ICAP model and the digital inverted classroom was held in the 2020 winter semester; the interprofessional practical training was added in the 2021 summer semester; and the interprofessional tandem job shadowing at a primary care practice in the 2021 winter semester. Attitudes toward interprofessional learning, among other things, was measured in the evaluation using the SPICE-2D questionnaire (Student Perceptions of Physician-Pharmacist Interprofessional Clinical Education). Results: In the first three semesters, a total of 105 students (46 pharmacy, 59 medicine) participated in the project, of which 78 participated in the evaluation (74% response rate). The students stated, in particular, that they had learned about the competencies and roles of the other profession and desired additional and more specific preparatory materials for the course sessions. The SPICE-2D questionnaire showed high values for both groups of students already in the pre-survey and these increased further as a result of the project. Conclusion: Joint case-based learning could be implemented under the conditions imposed by the pandemic. Online teaching is a low-threshold means to enable interprofessional exchange.

Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure-Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli.

Minimal inhibitory concentration-based pharmacokinetic/pharmacodynamic (PK/PD) indices are commonly applied to antibiotic dosing optimisation, but their informative value is limited, as they do not account for bacterial growth dynamics over time. We aimed to comprehensively characterise the exposure-effect relationship of levofloxacin against Escherichia coli and quantify strain-specific characteristics applying novel PK/PD parameters. In vitro infection model experiments were leveraged to explore the exposure-effect relationship of three clinical Escherichia coli isolates, harbouring different genomic fluoroquinolone resistance mechanisms, under constant levofloxacin concentrations or human concentration-time profiles (≤76 h). As an exposure metric, the 'cumulative area under the levofloxacin-concentration time curve' was determined. The antibiotic effect was assessed as the 'cumulative area between the growth control and the bacterial-killing and -regrowth curve'. PK/PD modelling was applied to characterise the exposure-effect relationship and derive novel PK/PD parameters. A sigmoidal Emax model with an inhibition term best characterised the exposure-effect relationship and allowed for discrimination between two isolates sharing the same MIC value. Strain- and exposure-pattern-dependent differences were captured by the PK/PD parameters and elucidated the contribution of phenotypic adaptation to bacterial regrowth. The novel exposure and effect metrics and derived PK/PD parameters allowed for comprehensive characterisation of the isolates and could be applied to overcome the limitations of the MIC in clinical antibiotic dosing decisions, drug research and preclinical development.

Quantification of persister formation of Escherichia coli leveraging electronic cell counting and semi-mechanistic pharmacokinetic/pharmacodynamic modelling.

BACKGROUND: Persister formation of Escherichia coli under fluoroquinolone exposure causes treatment failure and promotes emergence of resistant strains. Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of data obtained from in vitro infection model experiments comprehensively characterizes exposure-effect relationships, providing mechanistic insights. OBJECTIVES: To quantify persister formation of E. coli under levofloxacin exposure and to explain the observed growth-kill behaviour, leveraging electronic cell counting and pharmacokinetic/pharmacodynamic modelling. METHODS: Three fluoroquinolone-resistant clinical E. coli isolates were exposed to levofloxacin in static and dynamic in vitro infection model experiments. Complementary to plate counting, bacterial concentrations over time were quantified by electronic cell counting and amalgamated in a semi-mechanistic pharmacokinetic/pharmacodynamic model (1281 bacterial and 394 levofloxacin observations). RESULTS: Bacterial regrowth was observed under exposure to clinically relevant dosing regimens in the dynamic in vitro infection model. Electronic cell counting facilitated identification of three bacterial subpopulations: persisters, viable cells and dead cells. Two strain-specific manifestations of the levofloxacin effect were identified: a killing effect, characterized as a sigmoidal Emax model, and an additive increase in persister formation under levofloxacin exposure. Significantly different EC50 values quantitatively discerned levofloxacin potency for two isolates displaying the same MIC value: 8 mg/L [EC50 = 17.2 (95% CI = 12.6-23.8) mg/L and 8.46 (95% CI = 6.86-10.3) mg/L, respectively]. Persister formation was most pronounced for the isolate with the lowest MIC value (2 mg/L). CONCLUSIONS: The developed pharmacokinetic/pharmacodynamic model adequately characterized growth-kill behaviour of three E. coli isolates and unveiled strain-specific levofloxacin potencies and persister formation. The mimicked dosing regimens did not eradicate the resistant isolates and enhanced persister formation to a strain-specific extent.

Decoding (patho-)physiology of the lung by advanced in vitro models for developing novel anti-infectives therapies.

Advanced lung cell culture models provide physiologically-relevant and complex data for mathematical models to exploit host-pathogen responses during anti-infective drug testing.