The FICI paradigm: Correcting flaws in antimicrobial in vitro synergy screens at their inception

Abstract

Antibiotics have become the corner stone of modern medicine. However, our society is currently facing one of the greatest challenges of its time: the emergence of antimicrobial resistance. It is estimated that if no new therapies are implemented by 2050, 10 million people will die worldwide every year as a result of infections caused by bacteria resistant to current antibiotics; new antimicrobials are thus urgently needed. However, drug development is a tedious and very costly endeavor of hundreds of millions that can take up to 15-20 years from the bench discovery to the bedside. Under this scenario, drug repurposing, which consists in identifying new uses for old, clinically approved drugs, has gathered momentum within the pharmaceutical industry. Because most of these drugs have safety and toxicity information packages available, clinical evaluation could be done in a much shorter period than standard timelines. Synergistic combinations of these clinically approved drugs could also be a promising approach to identify novel antimicrobial therapies that might provide rational choices of available drugs to shorten treatment, increase efficacy, reduce toxicity, prevent resistance and treat infections caused by drug-resistant strains. However, although simple in its conception, translating results from in vitro synergy screens into in vivo efficacy or the clinical practice has proven to be a paramount challenge. In this Commentary, we will discuss common flaws at the inception of synergy research programs, with a special focus on the use of the Fractional Inhibitory Concentration Index (FICI), and evaluate potential interventions that can be made at different developmental pre-clinical stages in order to improve the odds of translation from in vitro studies.

Antimicrobial Synergy Testing: Comparing the Tobramycin and Ceftazidime Gradient Diffusion Methodology Used in Assessing Synergy in Cystic Fibrosis-Derived Multidrug-Resistant Pseudomonas aeruginosa

“…In CF patient management, there is the continuous emergence of multi-/pan-drug-resistant (MDR/PDR) strains, especially Pseudomonas aeruginosa , due to the prolonged and frequent administration of antimicrobial agents that are used in the treatment of pulmonary exacerbations [ 1 , 2 , 4 , 5 ]. The emergence of these MDR/PDR phenotypes, resistant to several classes of antimicrobials, impacts the therapeutic options in clinical practice [ 13 ]. As a result, in chronic pulmonary exacerbations management, physicians are compelled to employ combination therapy using ≥2 antibiotics, of which the inhibitory effects of the antibiotics used together are greater than the sum of each agent’s activity in monotherapy [ 14 ].…”

“…As a result, in chronic pulmonary exacerbations management, physicians are compelled to employ combination therapy using ≥2 antibiotics, of which the inhibitory effects of the antibiotics used together are greater than the sum of each agent’s activity in monotherapy [ 14 ]. There is a dearth of evidence on the best antimicrobial combination that will give a positive outcome [ 4 , 6 , 7 , 13 ] in clinical management, as the response of P. aeruginosa to various antimicrobial combinations has been shown to be unpredictable [ 11 ]. This is further confounded by the lack of in vitro synergy testing standardization, and the absence of gold standards.…”

“…There is currently no clear consensus on the gold standard for method evaluation, and no agreement exists on the best method. Several methods have been described and evaluated, for agreement with checkerboard or time-kill assays, as reference standards using numerous bacteria/antimicrobial combinations [ 13 ]. The time-kill method has been shown to yield high concordance in various studies, but because it produces dynamic and longitudinal information that cannot be obtained by other methods, its use as the gold standard for synergy testing is debatable [ 17 ].…”

Nitrofurantoin Combined With Amikacin: A Promising Alternative Strategy for Combating MDR Uropathogenic Escherichia coli

“…The increasing prevalence of antibiotic-resistant uropathogens has begun to limit the effectiveness of our existing antibiotic arsenal (Barber et al, 2013). Combinations of antibiotics are commonly used in medicine to broaden the antimicrobial spectrum and generate synergistic effects and this therapy has proven effective against MDR bacteria (Gomara and Ramon-Garcia, 2019). For example, the use of oral cephalosporin and b-lactamase inhibitor combinations for ESBL-producing Enterobacteriaceae UTI (Stewart et al, 2020).…”

“…Bacterial counts were determined based on the quantitative cultures on MHA plates. Synergy was defined as achieving a ≥ 2 log 10 cfu/ mL reduction in bacterial growth at 24 h with the combination compared with the most active individual drug concentration used on its own (Gomara and Ramon-Garcia, 2019). Three independent experimental runs were performed.…”