In the past, the dose finding process during antibacterial drug development depended on simple MIC testing and basic pharmacokinetic data from blood samples derived from healthy volunteers. Clinical confirmation of these data did not meet today’s standards of science. Recommended dosing regimens were more likely marketing decisions than based on rational basics (J. Mouton et al 2011).

Over the past twenty years scientists developed sophisticated methods in pharmacokinetics and pharmacodynamics that shaped the drug development process. Regulatory agencies such as EMA and FDA have recognised the power of the relationship of pharmacokinetics and pharmacodynamics (PK/PD) and issued guidance documents that highlight the need for determining appropriate dosing regimens based on this knowledge.

New game-changing methods and knowledge to define the appropriate dosage regimens of antibacterial drugs:
– Analytical methods to determine unbound drug concentrations
– PK variability in patients
– Population PK models
– Dynamic complex PD models in vitro
– Predictability of PK/PD models in the clinical situation
– Need for individualised dosing
– Therapeutic drug monitoring

Revived iv antibiotics for critically ill patients

Antibiotic Indication Knowledge gap Activities
Colistin (available across EU) Infections due to extensively drug resistant Gram-negative bacteria · Randomised controlled clinical studies

·Combinations (efficacy, prevention of resistance)

·Fine-tuning of dosing regimens
· TDM· In vitro testing methods, breakpoints

· Academic “redevelopment” is ongoing: PK, PK/PD, clinical efficacy and safety, breakpoints· Disseminating new knowledge to clinicians

· Assessing and updating regulatory information

Fosfomycin iv (limited availability) Infections due to extensively drug resistant Gram-negative bacteria, combination therapy · PK/PD· Optimised dosing· Randomised controlled clinical studies · Few activities (clinical studies) especially In Greece
Temocillin (only available in Belgium and UK) Infections due to multi- drug resistant enterobacteriaceae, esp. ESBL, carbapenem-sparing therapy · Increasing dosage

· Randomised controlled clinical studies

· Hardly any activities

Intravenous minocycline will be developed for Acinetobacter infections (MIC90 8 mg/L) in the US. Resistance to minocycline mostly determined by tetB is well known.

Intravenous minocycline is not available in Europe.

Revived oral antibiotics for out-patients

Antibiotic Indication Knowledge gap Activities
Nitrofurantoin (available across Europe) Acute lower urinary tract infections due to multidrug resistant pathogens · PK/PD· Safety in short-term use· Randomised controlled clinical studies · Limited academic “redevelopment” is ongoing: PK, PK/PD, resistance, clinical efficacy and safety
Pivmecillinam (limited availability) Urinary tract infections due to ESBL-producing enterobacteriaceae · Randomised controlled clinical studies in ESBL situations No activities
Minocycline (available across Europe but often approved only for acne) Community-acquired skin and soft tissue infections due to MRSA, alternative to linezolid · PK/PD· Randomised controlled clinical studies · Limited academic “redevelopment” is ongoing: PK, PK/PD, resistance, clinical efficacy and safety

An oral formulation of fusidic acid is redeveloped in the US for the treatment of acute bacterial skin and skin structure infections using a loading dose strategy. As fusidic acid is a single target agent the rapid emergence of resistance is of concern. The loading dose strategy does not solve the problem but defers the regrowth of resistant subpopulations beyond 4-5 days according to PK/PD models.

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