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.
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.
- Rodvold K. Approaches to target priority Gram-negative bacteria: building a better toolbox. Symposium presented at ASM Microbe 2018; 2018; Atlanta, GA.
- CenterWatch. Zerbaxa (cefotolozane + tazobactam). 2018. https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100057/zerbaxa-ceftolozane–tazobactam-. Accessed 6/26/2018.
- Allergan. FDA approves AVYCAZ(R) for the treatment of patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. 2018; https://www.allergan.com/news/news/thomson-reuters/fda-approves-avycaz-ceftazidime-and-avibactam-for.aspx. Accessed 6/26/2018.
- CenterWatch. Vabomere (meropenem and vaborbactam). 2018. https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100222/vabomere-meropenem-and-vaborbactam. Accessed July 2, 2018.
- Krause K, Serio A, Kane T, Connolly L. Aminoglycosides: an overview. Cold Spring Harb Perspect Med. 2016;6(6).
- Falagas ME, Mavroudis AD, Vardakas KZ. The antibiotic pipeline for multi-drug resistant gram negative bacteria: what can we expect? Expert Rev Anti Infect Ther. 2016;14(8):747-763.
- Doi Y, Wachino JI, Arakawa Y. Aminoglycoside resistance: the emergence of acquired 16S ribosomal RNA methyltransferases. Infect Dis Clin North Am. 2016;30(2):523-537.
- Zhanel GG, Lawson CD, Zelenitsky S, et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev Anti Infect Ther. 2012;10(4):459-473.
- Cloutier D, Miller L, Komirenko A, et al. Plazomicin versus meropenem for the treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP): results of the EPIC study. Poster presented at 27th ECCMID; April 22, 2017; Vienna, Austria.
- Achaogen. Update — ZemdriTM (plazomicin) approved by FDA for the treatment of adults with complicated urinary tract infections (cUTI). 2018. http://investors.achaogen.com/news-releases/news-release-details/update-zemdritm-plazomicin-approved-fda-treatment-adults?releaseid=1070946. Accessed July 10, 2018.
- Lob S, Hoban DJ, Hackel M, Young K, Motyl M, Sahm D. Activity of ceftolozane-tazobactam and comparatos against P. aeruginosa from patients in different risk strata — SMART United States 2016-2017. Poster presented at ASM Microbe 2018; June 8, 2018; Atlanta, GA.
- Ito-Horiyama T, Ishii Y, Ito A, et al. Stability of novel siderophore cephalosporin s-649266 against clinically relevant carbapenemases. Antimicrob Agents Chemother. 2016;60(7):4384-4386.
- Kohira N, West J, Ito A, et al. In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Antimicrob Agents Chemother. 2016;60(2):729-734.
- Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2016;60(12):7396-7401.
- Tillotson GS. Trojan horse antibiotics — a novel way to circumvent gram-negative bacterial resistance? Infect Dis (Auckl). 2016;9:45-52.
- Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol compared with imipenem/cirastatin in the treatment of adults with complicated urinary tract infections with or without pyelonephritis or acute uncomplicated pyelonephritis: results from a multicenter, double-blind, randomized study. Poster presented at 27th ECCMID; April 22, 2017; Vienna Austria.
- Portsmouth S, van Veenhuyzen D, Echols R, et al. Clinical response of cefiderocol compared with imipenem/cilastatin in the treatment of adults with complicated urinary tract infections with or without pyelonephritis of acute uncomplicated pyelonephritis: results from a multicenter, double-blind, randomized study (APEKS-cUTI). Poster presented at IDWeek 2017; October 7, 2017; San Diego, CA.
- Zavante. Zavante Therapeutics ZOLYD met primary endpoint in pivotal ZEUS study for treatment of complicated urinary tract infections. 2017. https://www.zavante.com/zavante-therapeutics-zolyd-met-primary-endpoint-in-pivotal-zeus-study-for-treatment-of-complicated-urinary-tract-infections/. Accessed 6/25/2017.
- Horn P, Tsai L, Solomkin J, Evans D, Gardovskis J. Results of IGNITE-4: a phase-3 study to evaluate the efficacy and safety of eravacycline versus meropenem in complicated intraabdominal infections. Oral presentation presented at 28th ECCMID; 2018; Madrid, Spain.
- Solomkin J, Evans D, Slepavicius A, et al. Assessing the efficacy and safety of eravacycline vs ertapenem in complicated intra-abdominal infections in the investigating gram-negative infections treated with eravacycline (IGNITE 1) trial: a randomized clinical trial. JAMA Surg. 2017;152(3):224-232.
- Lucasti C, Vasile L, Sandesc D, et al. Phase 2, dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother. 2016;60(10):6234-6243.
- Sims M, Mariyanovski V, McLeroth P, et al. Prospective, randomized, double-blind, phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother. 2017;72(9):2616-2626.
- Carpenter J, Neidig N, Thornsberry T, et al. In vitro susceptibility of recent carbapenem-resistant Enterobacteriaceae to imipenem-relebactam. Poster presented at ASM Microbe 2018; June 9, 2018; Atlanta, GA.
- Kulengowski B, Burgess D. Imipenem-relebactam activity against carbapenem-resistant Enterobacteriaceae at a tertiary referral center. Poster presented at ASM Microbe 2018; June 9, 2018, 2018; Atlanta, GA.
- Lob S, Kazmierczak K, Hackel M, Young K, Motyl M, Sahm D. Activity of imipenem-relebactam against multidrug-resistant and KPC-positive Enterobacteriaceae from the United States – SMART 2015-2017. Poster presented at ASM Microbe 2018; June 9, 2018; Atlanta, GA.
- Lob S, Kazmierczak K, Young K, et al. Activity of imipenem-relebactam against multidrug-resistant and KPC-positive Enterobacteriaceae from Europe – SMART 2015-2017. Poster presented at ASM Microbe 2018; June 9, 2018.
- Lob S, Hackel M, Kazmierczak K, Young K, Motyl M, Sahm D. Activity of imipenem-relebactam against multidrug-resistant P aeruginosa from the United States – SMART 2015-2017. Poster presented at ASM Microbe 2018; June 9, 2018; Atlanta, GA.
- Lob S, Hackel M, Young K, et al. Activity of imipenem-relebactam against multidrug-resistant P aeruginosa from Europe – SMART 2015-2017. Poster presented at ASM Microbe 2018; June 9, 2018; Atlanta, GA.
- Ditch K, Newman J, Ismailyan S, Fyfe C, Tsai L. Microbiological efficacy of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including MDR isolates: a pooled analysis from IGNITE1, IGNITE4, two phase 3 trials of complicated intra-abdominal infection. Poster presented at ASM Microbe 2018; June 9, 2018; Atlanta, GA.
- Teixeira-Santos R, Costa-de-Oliveira S, Silva-Dias A, et al. FASTinov(R) kits for AST and detection of main mechanisms of resistance on Gram-negative bacilli directly from positive blood cultures – performance evaluation. Poster presented at ASM Microbe 2018; June 10, 2018; Atlanta, GA.
- Costa-de-Oliveira S, Teixeira-Santos R, Silva-Dias A, Oliveira I, Rodrigues A, Pina-Vaz C. Flow cytometry antimicrobial susceptibility test (FAST) directly on positive blood cultures for Pseudomonas aeruginosa. Poster presented at ASM Microbe; June 10, 2018; Atlanta, GA.
- Quintas S, Teixeira-Santos R, Costa-de-Oliveira S, et al. Rapid susceptibility evaluation of ceftalozane/tazobactam by flow cytometry directly from positive blood cultures. Poster presented at ASM Microbe 2018; June 10, 2018; Atlanta, GA.
- Banerjee R, Dylla B, Komarow L, et al. Accelerate Pheno system (AXDX) performance during a randomized clinical trial evaluating rapid identification and antimicrobial susceptibility testing for Gram-negative bacteremia (RAPIDS-GN). Poster presented at ASM Microbe 2018; June 8, 2018; Atlanta, GA.
- Schneider J, Emery C, Davis T, et al. Direct antimicrobial susceptibility testing of positive blood cultures comparing the Accelerate PhenoTM and Vitek(R)2 systems. Poster presented at ASM Microbe 2018; June 10, 2018; Atlanta, GA.
- McCullough S, Mathers A, Brewster F, Poulter M, Elliott Z, Cox H. Evaluation of a novel microbiologic rapid diagnostic system on antimicrobial selection for Gram-negative bacillary bloodstream isolates. Poster presented at ASM Microbe 2018; June 10, 2018; Atlanta, GA.
- Cossette S, Torres M, Lechner J, Connelly C. Rapid detection of OXA β-lactamases by multiplex real-time PCR. Poster presented at ASM Microbe 2018; June 8, 2018; Atlanta, GA.
- Pandeya D, Dittman C, Boatsmann E, Bryant C, Lehr N, Strawn D. Outcomes of rapid identification of bacterial isolates from positive blood cultures using Verigene(R) nucleic acid test in combination with an antibiotic stewardship program. Poster presented at ASM Microbe 2018; June 8, 2013; Atlanta, GA.