George Tetz

and 4 more

INTRODUCTIONConventional phenotypic or genotypic antimicrobial susceptibility testing (AST) frequently fails to identify optimal and effective antibiotics (1, 2). In patients with recurrent urinary tract infections (UTIs), antibiotics selected with these tests frequently fail to eradicate infections resulting in relapses (3). One of the reasons for such failure is the reliance on the antibiotic response of the lead UTI pathogen within a pure bacterial culture. For example, conventional AST neglects the occurrence of multispecies biofilms during UTI, where bacteria are up to 1,000 times more tolerant to antimicrobials than corresponding planktonic cells (4, 5, 6). Moreover, the lead pathogen in multispecies biofilms could be additionally protected by collective antibiotic resistance, when an antibiotic resistance factor released by even non-virulent bacteria, which are often fewer in number, may protect an entire community (7). Another issue concerning the selection of antibiotics effective only against the lead pathogen is related to the difficulty in definitively establishing the pathogenicity of certain bacteria. For example, rare pathogens such as Bacillus spp., Kluyvera spp., and Herbaspirillum spp. have only recently been classified as pathogenic (8–10). Finally, standard AST is unable to detect persisters or account for inter-microbial communication via quorum sensing, Teazeled (TezR) receptors, and the TR-receptor system that upregulate resistance genes (11, 12, 13).The recently developed AtbFinder overcomes the above limitations (14). By recapturing polymicrobial biofilms from the biosamples it can identify effective and ineffective antibiotics by employing a “whole community response” to antibiotics instead of filtering a single lead bacterium. AtbFinder takes into consideration critical “real-life” factors required for the effective selection of antibiotics, such as biofilm growth, the presence of persisters, modulation of antibiotic resistance by quorum sensing and TezRs, and collective antibiotics resistance, not taken into consideration by routine AST.AtbFinder is a 48-well plate filled with proprietary developed TGV agar that supports growth of a diverse bacterial population. In each well, the agar is supplemented with one or several antibiotics at a concentration that reflects their penetration into different tissues. Biosamples are plated directly on the agar and do not require isolation of a pure culture. Following incubation at 37 °C for 4 h, bacterial growth on the agar surface determines the effectiveness of antibiotic treatment. AtbFinder delivers a result within 4 h, which allows patients with serious bacterial infections to receive effective antibiotic therapy within a day. Different types of AtbFinder have been developed for the treatment of lung, urinary, skin, and soft tissue infections, differing in the content of antibiotics tested and their concentration added to the agar which reflect the particularities of their PK/PD for different tissues.In pilot trials on patients with lung infections, antibiotics selected with AtbFinder developed for pulmonary diseases successfully eradicated multidrug-resistant gram-positive and gram-negative bacteria in patients with cystic fibrosis, who had been unsuccessfully treated with multiple antibiotic courses for years (15). Moreover, optimization with AtbFinder halved the total number of antibiotics administered to these patients. In the present report, we describe a clinical case, whereby AtbFinder was used successfully to select antibiotics for a patient with recurrent UTI.