Background Rapid blood culture diagnostics are costly and of unclearbenefit for patients with Gram-negative bacilli (GNB) bloodstream infections (BSIs). We conducted a multicenter, prospective, randomized controlled trial comparing outcomes of patients with GNB BSI who had blood culture testing with standard of care (SOC) culture and antimicrobial susceptibility testing (AST) versus rapid organism identification (ID) and phenotypic AST using the Accelerate Pheno™ System (RAPID). Methods Patients with positive blood cultures with Gram stains showing GNB were randomized to SOC testing with antimicrobial stewardship review (AS) or RAPID with AS, at two medical centers between 10/2017-10/2018. The primary outcome was time to first antibiotic modification within 72 hours of randomization. Results Of 500 randomized subjects, 448 were included (226 SOC, 222 RAPID). Mean (S.D.) hours to results was faster for RAPID than SOC for organism ID [2.7 (1.2) vs 11.7 (10.5), p < 0.001] and AST [13.5 (56) vs. 44.9 (12.1), p<0.001]. Median (IQR) hours to first antibiotic modification was faster in the RAPID vs. SOC arm for overall antibiotics [8.6 (2.6, 27.6) vs. 14.9 (3.3, 41.1), difference 6.3, p=0.02] and Gram-negative antibiotics [17.3 (4.9, 72) vs. 42.1 (10.1, 72), difference 24.8, p<0.001]. Median (IQR) hours to antibiotic escalation was faster in the RAPID vs. SOC arm for antimicrobial-resistant BSIs [18.4 (5.8, 72) vs. 61.7 (30.4, 72), difference 43.3, p=0.01]. There were no statistically significant differences between the arms in patient outcomes including mortality and length of stay. Conclusion Rapid organism ID and phenotypic AST led to faster changes in antibiotic therapy for Gram-negative BSIs. (Funded by the U.S. NIH UM1AI104681; ClinicalTrials.gov number, NCT03218397.)

The production of β-lactamase is the most common mechanism of resistance to β-lactam antibiotics among gram-negative bacteria. Extended-spectrum β-lactamases (ESBLs) are capable of hydrolyzing most penicillins, extended-spectrum cephalosporins, and aztreonam, but their activity is suppressed in the presence of a β-lactamase inhibitor. Serious infections with ESBL-producing isolates are associated with high rates of mortality, making early detection and adequate medical management essential to ensure optimal patient outcomes. Much controversy has centered on the recommendations for testing and reporting of antibiotic susceptibility of potential ESBL-producing organisms. The latest version of the Clinical Laboratory Standards Institute (CLSI) susceptibility reporting guidelines, published in 2010, no longer advocates for phenotypic testing of ESBL-producing isolates. From newer studies demonstrating a correlation between organism minimum inhibitory concentration (MIC) and clinical outcome, along with pharmacokinetic/pharmacodynamic (PK/PD) modeling demonstrating the importance of the MIC to achieving therapeutic targets, the CLSI has assigned lower susceptibility breakpoints for aztreonam and most cephalosporins. The new guidelines recommend using the lower MIC breakpoints to direct antibiotic selection. This article reviews the microbiology and epidemiology of ESBLs, the recent change in CLSI susceptibility reporting guidelines for ESBLs, and the clinical and PK/PD data supporting the relationship between in vitro susceptibility and clinical outcome. Finally, considerations for antimicrobial selection when treating patients with infections caused by ESBL-producing organisms from various sources are discussed.

No abstract

No abstract