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  • Periodic Report Summary 3 - AIDA (Preserving old antibiotics for the future : assessment of clinical efficacy by a pharmacokinetic/pharmacodynamic approach to optimize effectiveness and reduce resistance for off-patent antibiotics)

Periodic Report Summary 3 - AIDA (Preserving old antibiotics for the future : assessment of clinical efficacy by a pharmacokinetic/pharmacodynamic approach to optimize effectiveness and reduce resistance for off-patent antibiotics)

Project Context and Objectives:
In an era of increasing emergence of drug resistance (EDR) and lack of new antibiotics, old off-patent antibiotics are increasingly being prescribed to patients. However, many of these were developed in an age before the advent of a structured process for drug assessment and approval, and the establishment of clinical efficacy and effectiveness in randomized controlled trials in particular. The AIDA project aims to answer the question of clinical effectiveness and optimal dosing of off-patent antibiotics for infections caused by multiple drug resistant (MDR) bacteria in three randomized controlled clinical trials (WP1,2,3). In a multidisciplinary approach the exposure response relationships for each antibiotic will be elucidated by including pharmacokinetic (PK), pharmacodynamic (PD) and microbiological studies, including emergence of drug resistance (WP4). The project addresses the optimization of treatment of infections caused by MDR pathogens that impose a major burden of disease in Europe and the rest of the world by selecting 5 off-patent-antibiotics - colistin, fosfomycin, nitrofurantoin, minocyclin and rifampicin that are increasingly being used without clear evidence with respect to their effectiveness, duration of therapy and issues of EDR. Common to all the clinical trials proposed in this project is the selection of a clinically-relevant patient population; randomized controlled trial design to minimise bias; assessment of clinically-relevant outcomes for the individual patient, PK/PD assessment and correlation between PK/PD parameters and clinical outcomes, including efficacy, toxicity and EDR.

In the first trial (WP1) the efficacy of colistin alone is compared to colistin plus imipenem for severe infections caused by carbapenem-resistant bacteria, the second trial (WP2) compares fosfomycin vs. nitrofurantoin for the treatment of lower urinary tract infection in women at high risk of antibiotic-resistant pathogens and in the third trial (WP3) antimicrobial oral treatment with minocycline plus rifampicin is compared with oral treatment with linezolid for complicated skin and soft tissue infections (cSSTI) due to MRSA. The trials are powered to assess outcomes that are relevant to patients. In a separate project component PK/PD issues are covered and are considered an essential element that interrelate synergistically with the clinical studies (WP4). During each of the clinical trials, PK studies are performed in all or a subset of patients to determine drug exposures and the variation thereof, as well as the impact of gender and age. Using population PK modelling based on these substudies, drug exposures in each individual patient are estimated. In parallel, PK/PD relationships are studied based on PK data derived from microdialysis as well as preclinical models including animal systems. The results thereof will be used to refine exposure response relationships but also to study effects of exposure that are not readily observed in the trials. This aids to delineate optimal exposures and drug dosing. Similarly, EDR is studied in preclinical studies and in the trials by obtaining population resistance profiles and correlates with exposures. The dissemination of project results to professional groups and the public in general, communication to policymakers, and implementation of results in national formularies is considered an important aspect and this is covered by a separate workpackage (WP5). The overall objective of the studies is to integrate all aspects that play a role in defining the optimal antibiotic choices and dosing regimens of the off-patent antibiotics in the treatment of infections caused by multi-resistant bacteria.

Project Results:
The main goal of the project AIDA is to gain preclinical and clinical data of 5 off-patent antimicrobials to allow optimizing dosing regimens. To that end, 3 clinical trials (WP1-3) and preclinical studies (WP4) are performed. The dissemination of results is handled in WP5. Below, for each of the WPs, a brief description of the work and main results so far are described.

The protocol of the randomized controlled trial (RCT) comparing colistin monotherapy vs. colistin-meropenem combination therapy has been published in BMJ Open, explaining the rationale for the study design, outcome selection and ethical aspects of the trial (doi:10.1136/bmjopen-2015-009956).
The RCT is nearing completion. As of now, 345 patients have been recruited. As no interim analysis was planned results are not available. However, descriptive data have been analyzed to guide protocol amendments. Among patients completing follow-up, 275/339 (81%) were treated per protocol (patients surviving at least 48 hrs. and receiving at least 5 days of the assigned antibiotic regimen, or until death if dead between days 3-5, without concomitant antibiotics). Acinetobacter is the dominant pathogen in 273 (80.5%) of patients. Mortality was 114/339 (33.6%) on day 14 and 153/328 (46.6%) on day 28. The primary composite outcome of treatment success on day 14 was observed only in 90/339 (26.5%) of patients, while in our original sample size calculations we have planned for a success rate of 62%. Colistin and meropenem drug levels are being analysed in batches and preliminary results are available (see WP4). All microbiological samples have been submitted to the central laboratory for analysis after end of recruitment.

Since November 2014, Work Package 2 has continued its recruitment steadily. The Geneva site has screened over 200 patients and included 129; the Lodz site has screened over 250 patients and included 163; and the Tel Aviv site has screened 130 to include 108. We have thus included 400 patients. The gap between targeted and actual recruitment is steadily being narrowed. In November 2015, the study had reached only 50% of the target recruitment; currently we are at 75% of the target.
In addition to the ongoing randomized trial, WP2 members collaborated with other AIDA investigators to conduct an extensive systematic review and meta-analysis on nitrofurantoin’s efficacy and toxicity when given short-term for active urinary tract infections (UTI). This study was published in the Journal of Antimicrobial Chemotherapy (2015;70(9):2456-64) in June 2015. The same group of collaborators has now finished an equally exhaustive systematic review and meta-analysis of nitrofurantoin’s efficacy and toxicity when given long-term for UTI prophylaxis. The manuscript has been submitted to Clinical Microbiology and Infection and is currently under peer review.

The activities in the last year have, more or less, all involved the on-going RCT of minocycline plus rifampicin vs linezolid in MRSA SSSTI. Recruitment has been below target perhaps related to the declining incidence of MRSA infection. Further centres have been opened in Greece and the trial extended for a period of 6 months.

The main focus during this period was on pharmacokinetic and pharmacodynamic (PKPD) preclinical and clinical studies of nitrofurantoin and fosfomycin to further support PKPD analysis and dose justifications when the clinical trials are finished. For nitrofurantoin, extensive studies were performed using time-kill curves under various conditions. Surprisingly, it was found that activity and PKPD relationships are species dependent. A phase 1 type study to determine the pharmacokinetic profile of nitrofurantoin was completed and the pharmacokinetic analysis is currently being performed. An in vitro bladder model was set-up to simulate nitrofurantoin and fosfomycin concentrations over several days, including the effects of voiding. Preliminary results indicate faster emergence of resistance to fosfomycin than anticipated. Pharmacokinetics of fosfomycin in urine are being determined in an ongoing clinical trial.

A priority in 2015/2016 was raising awareness about the need to study and optimize the use of old antibiotics. The concept of AIDA was used as a model for “re-developing” old antibiotics and several articles were published in peer-reviewed journals. Meetings with EMA and a presentation at the biennial meeting of the Transatlantic Task Force on Antimicrobial Resistance (TATFAR) was well received and widely discussed. Face-face meetings with policy makers of several European countries to discuss the availability of old antibiotics and improve their usage enhanced AIDA’s visibility. Ongoing dialogues with professional societies helped to disseminate scientific findings of AIDA. A training course for physicians and the research community was organised in November 2015 with the support of the European Society for Clinical Microbiology and Infectious Diseases (ESCMID). In fruitful discussions with representatives of other EU funded projects, with regulatory agencies (EMA and FDA), and pharmaceutical companies we could demonstrate how AIDA was successful in recruiting critically ill patients with infections caused by most resistant pathogens though such studies are considered to be extremely difficult. Experiences gained by AIDA may influence the development of new antibiotics in a similar patient population. Our communication activities helped to broaden the discussions and provide input for development strategies of new antibiotics.

Potential Impact:
The expected results and impact of this program will be several, among others:
• Assessment of the effectiveness of off-patient antibiotics via randomized controlled trials with stringent endpoints that are relevant for “real life” patients
• Optimization of dosing regimens that will likely result in improved clinical outcome and in a lower propensity of EDR thus potentially saving lives
• Providing a scientific basis for an update of European breakpoints (EUCAST)
• Integration of evidence based project results in guidelines and formularies
• Cost-savings as a result of updated evidence and improved usage of off-patent antibiotics
• Supporting EMA with evidence based information regarding re-evaluation of old antibiotics
• Setting a validated standard for a systematic re-evaluation of off-patent antibiotics
• Serving as a model for alternative concepts of development of new antibiotics in the non-profit space

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