A European consortium of researchers studied five off-patent community and hospital antibiotics with modern methods. They integrated the results of three randomized controlled clinical trials with extensive non-clinical studies. The results of this collaborative European project showed that real-life clinical studies have less favorable results compared to company-sponsored trials with selected and homogenous patient populations. Based on the project results, dosage regimens need to be updated and the use of old antibiotics revisited.
Recognizing the urgent need to optimize the use of old antibiotics, the European Union funded the multinational collaborative project AIDA (PRESERVING OLD ANTIBIOTICS FOR THE FUTURE) to fill the knowledge gaps for five old antibiotics. The researchers from 11 European countries challenged routine usage patterns and dosing regimens that were developed decades ago on a trial-and-error basis. They raised these questions: is the common use of the antibiotic colistin in combination with another antibiotic better than used alone in critically ill patients? Is a single-dose regimen of fosfomycin as effective as conventional therapy with nitrofurantoin in uncomplicated bladder infection? Is the combination of the old antibiotics rifampicin+minocycline as effective as linezolid for orally treated skin infections caused by MRSA?
The AIDA project accomplished three randomized controlled trials with each comparing two antibiotic regimens in infections caused by multidrug-resistant bacteria. The trials were designed to reflect real-life situations in clinical practice. Each of these three clinical studies was linked to a variety of laboratory and animal studies supporting and understanding clinical trial results. The collaboration of researchers from different disciplines and the successful completion of the AIDA project highlights the capacity of academic groups to “re-develop” old antibiotics and integrate complex clinical studies with high quality non-clinical research.
“AIDA will challenge some usage patterns and old believe about dosing regimens and clinical practice,” summarized Johan Mouton, coordinator of AIDA and Professor at Rotterdam University. Colistin is an antibiotic that was not used for almost half a century but revived as effective treatment for the most resistant bacteria. Johan Mouton: “We used colistin in critically ill patients based on little knowledge from the 1950s”. The AIDA project completed recruitment of patients of the clinical trial and contributes evidence to the common clinical practice of combining colistin with a carbapenem in cases of carbapenem-resistant bacteria. Mical Paul, who is Head of Infectious Diseases at Rambam Health Care Campus in Tel Aviv and led the extremely difficult randomized controlled trial in Intensive Care Unit patients concluded: “Finding evidence based on a large randomized controlled clinical trial that is supported by sophisticated microbiological and pharmacokinetic information provides the foundation for best patient care”. Recruiting a high number of critically ill patients infected by the most resistant Gram-negative bacteria is regarded as extremely challenging or even impossible. The AIDA project completed such a trial due to the high motivation and dedication of the medical teams in Israel, Greece and Italy.
The convenient single-dose oral treatment with fosfomyin in uncomplicated cystitis was also challenged in the AIDA project. The randomized controlled clinical trial was successfully completed and the results will be published soon. Anecdotal data had indicated a low response rate of a single dose of oral fosfomycin. The clinical trial results of the AIDA project clarified this question. Supported by pharmacokinetic studies and computer simulations these results may trigger a change in usage and more studies to define the best dosing regimen of oral fosfomyin.
Old antibiotics are off patent and no formal responsibility is defined for updating the knowledge of these valuable drugs. AIDA produced vital integrated non-clinical and clinical data to strengthen our evidence-based confidence for using these old drugs in daily clinical practice. “AIDA helped to shed light on the usage of vital old antibiotics that may support further activities of regulatory authorities,” adds Johan Mouton.
The AIDA project officially ends this year and will continue to publish all details that were generated during its lifetime.