Despite the promise of these emerging antimicrobial agents, the time needed to identify infecting organisms and begin appropriate therapy remains a problem.  To optimize antimicrobial therapy, and also for the purposes of surveillance and antimicrobial stewardship, laboratories must be able to determine susceptibilities in as close to real time as possible. However, new susceptibility tests are not approved at the same time that drugs are. Thus, there is a lag between the appearance of a new antimicrobial agent on the market and the ability of microbiology laboratories to test for susceptibility to it. During that lag, clinicians are often stuck using drugs for which susceptibility can be tested only with research-use-only methods or by sending samples to central reference laboratories.

The good news is that rapid antimicrobial susceptibility testing (AST) has been receiving increasing attention. Several presentations at ASM Microbe 2018 focused on rapid phenotypic tests from blood samples. Pina-Vaz and colleagues presented several posters on the flow cytometry-based FASTinov® assay, which allows for the determination of antimicrobial susceptibility and the detection of enzymatic resistance to β-lactams.30 Compared with results from Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) microdilution protocols, FASTinov® results showed categorical agreement rates of at least 93% for Enterobacteriaceae,30 96% for A baumannii,30 and 95% for P aeruginosa.31 The highest error rates were reported for imipenem for Enterobacteriaceae,30 ceftazidime for A baumannii,30 meropenem for P aeruginosa,31 and piperacillin-tazobactam for all three, but error rates did not exceed 5%. In a late-breaking poster, this group reported an overall categorical agreement of 92% between FASTinov® and CLSI and EUCAST protocols for ceftolozane-tazobactam.32

Several groups also presented posters on the Accelerate Pheno System (AXDX). Banerjee and colleagues reported a preliminary analysis based on data from a randomized controlled trial comparing clinical outcomes among patients with Gram-negative bacteremia tested directly with AXDX vs that tested by standard-of-care culture and AST.33 The preliminary analysis found that AXDX detected 79% of Gram-negative organisms isolated from blood cultures and that 90% of organisms identified by standard-of-care testing were targets on the AXDX panel.33 The rate of discrepancies between AXDX and standard of care was low, ranging from 0% for very major errors to 6% for minor errors, and in most cases, the discrepancies were read by AXDX as less susceptible. Schneider and colleagues reported that AXDX performed comparably with Vitek2® testing, with categorical agreement ranging from 91.5% compared with direct-inoculation Vitek2® to 97.6% compared with traditional Vitek2® testing.34 However, the average testing time from time of blood culture was 9.0 hours for AXDX, compared with 13.0 hours for direct-inoculation Vitek2® and 35.7 hours for traditional Vitek2®. McCullough and colleagues reported that AXDX reduced time to organism identification by 24.1 hours and time for AST by 29.3 hours.35 However, they also noted that AXDX reported ceftriaxone and ampicillin-sulbactam as the narrowest agents against 46% of Escherichia coli and 39% of Klebsiella pneumoniae, thus offering limited opportunities for de-escalation of therapy.

Other posters at ASM Microbe 2018 reported on genotypic susceptibility testing. Cosette and colleagues reported on an assay that uses multiplex, real-time polymerase chain reaction to detect OXA β-lactamases with a sensitivity and specificity of 95% or higher.36 Pandeya and colleagues reported that implementation of the Verigene® nucleic acid test did not significantly shorten the length of time between blood collection and initiation of the first dose of antibiotic therapy.37 However, it was associated with shortened lengths of stay from 178 hours to 161.6 hours overall and from 170.8 hours to 158.3 hours for patients with Gram-negative bacterial infections.

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Newly approved and emerging agents offer hope for combating Gram-negative bacterial infections. However, some hospitals have already seen the emergence of resistance to ceftolozane-tazobactam and ceftazidime-avibactam, and ongoing delays in getting approved rapid AST assays to microbiology laboratories and in initiating appropriate antibiotic therapy could promote further resistance. It is inevitable that some resistance will be seen with each newly approved agent. Therefore, improved and rapid AST is needed to optimize how these agents are used and to direct them most effectively against the organisms they are most likely to target. Teamwork is also needed among clinicians, microbiology laboratories, primary care services, and antimicrobial stewardship teams to ensure that tests are ordered promptly and conducted in a timely fashion, with results returned to clinicians as soon as possible and support in place to help them interpret and act on those results. The wide breadth of ASM Microbe 2018 presentations reporting on new drugs against highly resistant pathogens and highly performing rapid susceptibility tests is especially encouraging. The challenge now will be incorporating these new weapons into rational patient management strategies.

Disclosure: Dr Clancy has received investigator-initiated research grant support from Merck, Pfizer, Melinta, Astellas, and Cidara.

References

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