Pharmacokinetics, pharmacodynamics and toxicodynamics
Adequate anti-infective treatment is extremely important to save the lives of patients with serious infections. D4 research develops optimised dosage regimens for anti-infectives to effectively kill the pathogen, while minimising emergence of resistance and potential adverse effects in patients. To achieve this, it is important to quantitatively determine the pharmacokinetics (PK), pharmacodynamics (PD) and toxicodynamics (TD) of the anti-infective drugs.
D4 research employs in vitro dynamic infection models (including the hollow fibre system), animal models and clinical studies to characterise the PK/PD/TD of anti-infectives. This is studied both for antimicrobial monotherapy and combinations, as many infections by resistant pathogens cannot be adequately treated by a single antimicrobial.
Minimising the development of microbial resistance and the risk of generating adverse effects are also key considerations. It is now well accepted that these objectives can be achieved through the application of PK/PD principles to optimise the dosage regimens of antimicrobial drugs.
D4 researchers are developing scientifically-based dosage recommendations for specific patient groups, such as ICU patients, renal replacement therapy patients and those with difficult-to-treat infections of the lungs, bone and urinary tract. These recommendations (such as for colistin, polymyxin B, beta-lactams, oxazolidinones, fusidic acid, and other antibiotic classes) are implemented in hospitals internationally. We are developing mechanism-based mathematical models that utilise the results from all studies, thereby enabling efficient translation of research outcomes into patient care.
D4's research on antimicrobial PK/PD/TD has been very well supported by the US National Institutes of Health and the Australian National Health and Medical Research Council.
Polymyxins and combinations
Because both colistin and polymyxin B came into clinical use more than 50 years ago (prior to the advent of modern drug development and regulatory procedures for approval of new drugs), virtually no information is available to guide their optimal clinical use.
D4 researchers in this area have been very active for more than a decade. D4 is an international leader in conducting PK, PD and PK/PD preclinical and clinical studies on the polymyxin class of antibiotics (colistin and polymyxin B), as well as on innovative polymyxin combinations involving beta-lactam antibiotics.
D4 research provides essential PK/PD/TD information required for optimising clinical use of colistin and polymyxin B monotherapy and combination therapy.
Beta-lactams, aminoglycosides, quinolones and their combinations
Beta-lactams are the largest (>40 clinically available) and most commonly used class of antibiotics, and have proven very safe. Aminoglycosides and quinolones are also frequently used against Gram-negative superbugs. However, emergence of resistance is common against these agents in monotherapy, and this has serious consequences—particularly in vulnerable patients such as the critically ill. Emergence of bacterial resistance is a serious global problem in both the hospital and community setting.
These combinations leverage mechanistic insights on synergistic killing and resistance prevention, as well as pharmacokinetic and clinical considerations. Combination regiments are specifically designed for pathogens with significant resistance mechanisms in the hospital and community setting.
Furthermore, in chronic infections (such as pulmonary infections in COPD and cystic fibrosis patients) bacteria can increase their mutation rates to become resistant even more quickly. Substantial gaps exist on mechanisms of synergy and optimal combination therapy.
D4 researchers are therefore rationally optimising such combinations to maximise bacterial killing, and minimise emergence of resistance and potential adverse effects in patients.
- Dr Jurgen Bulitta
- Dr Cornelia Landersdorfer