Old antibiotics – a new lease of life
A combination of multiple drug resistance (MDR) in bacteria and lack of new antibiotics has fuelled the use of antimicrobials developed before the advent of a structured process for clinical efficacy and effectiveness assessment. The AIDA project worked to assess effectiveness and optimal dosing of off-patent antibiotics for infections caused by MDR bacteria in three randomised controlled trials. Five off-patent antibiotics subject to study Researchers addressed the optimisation of treatment of infections caused by MDR pathogens that impose a major burden of disease on Europe and the rest of the world. Off-patent-antibiotics are increasingly being used without clear evidence on their effectiveness, duration of therapy and issues of emerging drug resistance (EDR). Importantly for patients, many of these were licensed many years ago when the rules were less stringent and knowledge to determine optimal dose using pharmacodynamics was not available. “As a result, the efficacy of many old drugs is not clearly established, nor is the dosing regimen,” explains project coordinator, Dr Johan Mouton. The AIDA project took a pharmacokinetic (PK) and pharmocodynamic (PD) approach together with microbiological studies, thereby including the pressing issue of drug resistance. Looking at exposure-response relationships, PK/PD, they have established safe and effective dosing. “With EDR issues an essential element of the research project, these studies will interrelate synergistically with the clinical studies,” Dr Mouton points out. Results will be used to refine exposure response relationships but also to study effects of exposure that are not readily observed in the trials. Randomised trials for three serious real-life resistance scenarios AIDA researchers chose microbial infections that were subject to potential inappropriate prescription for study, both in hospitals as well as in outpatients. Hospital acquired pneumonia causes severe infections due to carbapenem-resistant Gram-negative bacteria in patients in intensive care units. The major outcome of a trial with 345 patients was that the combination therapy, using meropenem and colistin, although often practiced, offered no benefit over colistin alone. The results were published recently in the journal Lancet Infectious Diseases. Community-acquired lower urinary tract infections are common and patients are increasingly at risk from MDR pathogens. The trial involving more than 400 patients compares efficacy of the old antibiotics fosfomycin with nitrofurantoin, the results of which will be published shortly. Together with the pharmacodynamic studies these results provide a clear message on how to use these drugs. Methicillin-resistant Staphylococcus aureus (MRSA), again often a community-acquired bacterium, causes skin and soft tissue infections. The AIDA randomised clinical trial has looked at the effectiveness of minocycline plus rifampicin versus linezolid. A so-called reserve antibiotic, linezolid is classed as one of those that should be used sparingly so it will remain effective against potentially intractable infections. Research impact and social significance Emphasising what is possibly the key result in the project, Dr Mouton outlines, “We have been able to finalise three large clinical trials initiated by investigators at a fraction of the cost of the typical industry-initiated trials, including those currently supported by the Innovative Medicines Initiative (IMI).” Impact of the assessment of the effectiveness of off-patent antibiotics means that the choice of antimicrobial as well as its dose can be optimised and there will be an improved clinical outcome with possibly lower EDR and cost. “Indeed, the outcome of the trial in lower urinary tract infections provides a clear indication that the choice of therapy has a profound impact on clinical outcome in one of the most common infectious diseases, which will benefit a large number of patients,” Dr Mouton stresses.
Keywords
AIDA, antibiotic, trial, off-patent, efficacy, drug resistance