Clinical And Laboratory Standards Institute Breakpoints Research Articles

Amoxicillin-clavulanate Breakpoints Against Enterobacterales: Rationale for Revision by the Clinical and Laboratory Standards Institute.

Amoxicillin-clavulanate (AMC) is among the most frequently prescribed antibiotics globally. It has broad antibacterial activity against gram-positive, gram-negative, and anaerobic bacteria, and has been utilized to treat infections caused by a broad range of pathogens. AMC breakpoints against Enterobacterales were initially set in the 1980s but since then increases in antibiotic resistance, advances in pharmacokinetic (PK)/pharmacodynamic (PD) analyses, and publication of additional clinical data prompted a reassessment by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing. Based on this contemporary reappraisal, the CLSI retained the Enterobacterales breakpoints but revised comments regarding dosing associated with use of the AMC breakpoints in the 2022 supplement of M100. This viewpoint provides insight into the CLSI breakpoint reevaluation process and summarizes the data and rationale used to support these revisions to the AMC Enterobacterales breakpoint.

In Vitro Activity of Dalbavancin and Fourteen Other Antimicrobial Agents Against Toxigenic Clostridioides Difficile Clinical Isolates in a Greek Tertiary-Care Hospital.

Clostridioides difficile is a major cause of healthcare-associated diarrhea worldwide. For years, metronidazole and vancomycin were considered the standard treatment for C. difficile infection (CDI). However, they are increasingly being associated with treatment failure and recurrence. In this study we investigated the in vitro activity of dalbavancin and fourteen other antimicrobials against 155 toxigenic C. difficile isolates originating from patients with C. difficile-associated diarrhea. Antimicrobial susceptibility was evaluated by the MIC Test Strip and the results were interpreted using both the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial susceptibility Testing (EUCAST) breakpoints. C. difficile isolates were fully susceptible to metronidazole, vancomycin, amoxicillin/ clavulanate, piperacillin/tazobactam, and tigecycline. All isolates were dalbavancin susceptible by the CLSI breakpoint (≤ 0.25 μg/ml) compared with 97.4% susceptibility by the EUCAST breakpoint (≤ 0.125 μg/ml). Dalbavancin demonstrated significantly lower MIC50 and MIC90 values compared to vancomycin (0.047 vs. 0.38 and 0.125 vs. 0.5, respectively, p < 0.001). Resistance rates to penicillin, ampicilin, cefoxitin, imipenem, meropenem, clindamycin, moxifloxacin, chloramphenicol, and tetracycline were 20%, 14.2% , 100%, 75.5%, 0.6%, 51%, 36.1%, 3.2%, and 14.8%, respectively. Multidrug-resistant (MDR) phenotypes were detected among 41.3% of the isolates. Dalbavancin exhibited potent activity against the isolates tested. As C. difficile is an important healthcare-associated pathogen, continued surveillance is required to monitor for development of resistance.

Assessment of cefiderocol disk diffusion versus broth microdilution results when tested against Acinetobacter baumannii complex clinical isolates.

The aim of this study was to evaluate the correlation between inhibitory zones and minimum inhibitory concentrations (MICs) when testing cefiderocol against Acinetobacter baumannii complex using disk diffusion and the broth microdilution (BMD) method according to the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. Four-hundred and sixty-eight non-duplicated A. baumannii complex clinical isolates were collected from 56 hospitals of the China Antimicrobial Surveillance Network from 2019 to 2021. BMD using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) and standard disk diffusion methods were performed according to CLSI guidelines. Results were interpreted according to the CLSI and EUCAST breakpoints. Categorical agreement (CA), minor error (mE), major error (ME), and very major error (VME) were calculated for disk diffusion methods. The susceptibilities of all A. baumannii complex isolates by BMD were 98.7% (CLSI) and 97.6% (EUCAST). For all A. baumannii complex isolates, CA was 98.1% (CLSI) and 97.0% (EUCAST), with 0.9% (CLSI) and 1.9% (EUCAST) of VME, respectively. For the carbapenem-susceptible A. baumannii complex, the CA was 100%, with no mE or VME using both CLSI and EUCAST breakpoints. For carbapenem-resistant A. baumannii complex, CA was 97.5% (CLSI) and 96.2% (EUCAST), with 1.1% (CLSI) and 2.5% (EUCAST) of VME, respectively. Regarding the difficult-to-treat resistance A. baumannii complex isolates, CA was 97.6% (CLSI) and 95.7% (EUCAST), with 1.2% (CLSI) and 3.1% (EUCAST) of VME, respectively. Cefiderocol disk diffusion was difficult to assess in this study. Very few isolates were resistant to cefiderocol by BMD using CLSI breakpoint, and these were categorized as susceptible with the disk diffusion test. This study did, however, show that the main proportion of A. baumannii isolates were susceptible to cefiderocol by BMD, including carbapenem-resistant A. baumannii. IMPORTANCE Carbapenem-resistant Acinetobacter baumannii is a major global health concern due to its high prevalence and limited treatment options. Cefiderocol is the only novel Food and Drug Administration (FDA)-approved β-lactam agent for the salvage treatment of carbapenem-resistant A. baumannii infection. Currently, a commercial automated susceptibility testing panel of cefiderocol is unavailable. Both the preparation of iron-depleted cation-adjusted Mueller-Hinton broth and the performance of broth microdilution are cumbersome in routine microbiology laboratories. A disk diffusion method is convenient for cefiderocol antimicrobial susceptibility testing, but limited data are available specifically for A. baumannii clinical isolates. Moreover, the Clinical and Laboratory Standards Institute published revisions to the A. baumannii cefiderocol disk diffusion breakpoints in 2022. Hence, we evaluated the performance of cefiderocol disk diffusion compared with the reference BMD against A. baumannii clinical isolates, especially those with cefiderocol zone diameters ≤ 14 mm.

A-280 Impact of 2022 CLSI Revised Piperacillin/Tazobactam Clinical Breakpoints on Enterobacterales Isolates Identified at a Tertiary Medical Center in Southern Taiwan

Abstract Background Piperacillin-tazobactam (TZP) is one of the most common antibiotics administered to hospitalized patients. Its broad activity against gram-negative, gram-positive, and anaerobic pathogens. The Clinical and Laboratory Standards Institute (CLSI) publishes revised TZP breakpoints in 2022. The purpose of this study was to evaluate the impact of changing the TZP breakpoint in a regional teaching hospital in southern Taiwan. Methods We retrospectively evaluated TZP for 1347 Enterobacterales isolates identified by MALDI-TOF (Bruker Daltonik, Bremen, Germany) between September 1, 2022, through December 31, 2022, at Chang Gung Memorial Hospital in Chiayi. Blood antimicrobial susceptibility testing was performed using an NMIC-411 panel on the BD Phoenix™ M50. The antibiotic susceptibility test of Enterobacterales from other sources of infection used the Disk diffusion method (Kirby-Bauer Method). Susceptibilities were assessed based on historic CLSI breakpoints in 2021 as well as the current CLSI breakpoints from the most recent CLSI MIC breakpoints, the 32th edition of document M100, published in 2022. Results We evaluated 1347 Enterobacterales isolates. Most isolates identified were Escherichia coli [n = 768 (57%)] and Klebsiella pneumoniae [n = 286(21.2%)]. The new TZP breakpoints reduced the percentage of strains that were previously judged to be susceptible by CLSI M100-S31 from 80.9%(1090/1347) to 50%(674/1347). The majority of isolates 674(50%) were susceptible; 416 (30.9%) isolates were susceptible-dose dependent and 257 (19.1%) were resistant to piperacillin/tazobactam using the new CLSI breakpoints. The results of the analysis of the source of infection found that the bacteria that had the greatest impact on the respiratory tract decreased from 43.6% to 12.7%, followed by the genitourinary tract infection decreased from 80.4% to 27%, bodily fluid infection decreased from 69.8% to 24.5%, and abscesses,wounds,pus decreased from 72.7% to 28.1%; The most insignificant are blood infection strains, from 83.1% to 81.3%. Conclusion Our results indicate an increase in resistance to Enterobacterales isolates tested. Non- susceptible to piperacillin/tazobactam from 19.1% to 50% using the revised CLSI breakpoints. The decreased susceptibilities make it clear that microbiology laboratories should accept new MIC breakpoints. Although our study has demonstrated decreased susceptibilities, there is no correlation with clinical outcomes. In conclusion, changes in breakpoints had a significant impact on the susceptibility of TZP for Enterobacterales isolates in our study. Understanding and evaluating the impact of the breakpoint changes is of paramount importance. Institutions should ensure that their breakpoints are up to date to allow for the most optimized treatment.

Antifungal Susceptibility Pattern of Candida glabrata from a Referral Center and Reference Laboratory: 2012-2022.

The prevalence of invasive candidiasis caused by non-Candida albicans has rapidly increased. Candida glabrata (Nakaseomyces glabrata) is an important pathogen associated with substantial mortality. Our study examined the antifungal temporal susceptibility of C. glabrata and cross-resistance/non-wild-type patterns with other azoles and echinocandins. Laboratory data of all adult patients with C. glabrata isolated from clinical specimens at the Mayo Clinic, Rochester, from 2012 to 2022 were collected. Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were used. We obtained 1046 C. glabrata isolates from 877 patients. Using CLSI and EUCAST breakpoints, 187 (17.9%) isolates and 256 (24.5%) isolates were fluconazole-resistant, respectively. Focusing on C. glabrata bloodstream infections, fluconazole-resistance ranged from 16 to 22%. Among those 187 fluconazole-resistant isolates, 187 (100%) and 184 (98.4%) isolates were also voriconazole and posaconazole non-wild-type, respectively, with 97 (51.9%) isolates deemed non-wild type for itraconazole. The fluconazole susceptibility pattern has not changed over the past decade. The proportion of fluconazole-resistant C. glabrata is relatively high, which could be due to the complexity of patients and fluconazole exposure. Itraconazole appears to be a compelling step-down therapy for fluconazole-resistant C. glabrata, given the high proportion of wild-type isolates. Further research to examine clinical outcomes is warranted.

In vitro activity of eravacycline and comparators against Gram-negative and Gram-positive bacterial isolates collected from patients globally between 2017 and 2020

To evaluate eravacycline (ERV) activity against Gram-negative and Gram-positive bacteria collected between 2017 and 2020 from worldwide locations. MIC determinations were performed using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology. ERV and tigecycline susceptibility was interpreted using United States Food and Drug Administration (FDA) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. Comparator susceptibility was interpreted using CLSI and EUCAST breakpoints. ERV MIC90 was 0.5 μg/mL against 12,436 Enterobacteriaceae isolates, which only increased to 1 μg/mL against multidrug-resistant (MDR) isolates (n=2931 (23.6%). Similar activity was shown against 1,893 Acinetobacter baumannii (MIC90 1 μg/mL) and 356 Stenotrophomonas maltophilia (MIC90 2 μg/mL). ERV was more active against Gram-positive bacteria: 415 Streptococcus pneumoniae (MIC90 0.008 μg/mL), 273 S. anginosus group (MIC90 0.015 μg/mL), 1,876 Enterococcus faecalis and 1,724 E. faecium (MIC90 2 μg/mL), 2,158 Staphylococcus aureus and 575 S. saprophyticus (MIC90 0.12 μg/mL), 1,143 S. epidermidis and 423 S. haemolyticus (MIC90 0.25 μg/mL). ERV MIC90 against methicillin-resistant staphylococci and vancomycin-resistant enterococci was similar to susceptible strains. However, ERV susceptibility varied between EUCAST or FDA against staphylococci, especially S. epidermidis (91.5% vs 47.2%), and vancomycin-resistant E. faecalis (98.3% vs 76.5%). This study reaffirms ERV's consistent broad-spectrum activity that has been evaluated since 2003. ERV remains a key agent for the treatment of bacterial infections, including resistant isolates, but urgent re-assessment of clinical breakpoints is required for staphylococci and enterococci.

Strategies for Updating Piperacillin-Tazobactam Breakpoints.

In this issue of the Journal of Clinical Microbiology, C. Manuel, R. Maynard, A. Abbott, K. Adams, et al. (J Clin Microbiol 61:e01617-22, 2023, https://doi.org/10.1128/JCM.01617-22) describe a multisite study evaluation of piperacillin-tazobactam (TZP) MIC testing on three U.S. Food and Drug Administration (FDA)-cleared antimicrobial susceptibility testing (AST) devices compared to the reference broth microdilution method for organisms belonging to Enterobacterales. Although overall performance of each of the three devices was comparable when applying either FDA or Clinical and Laboratory Standards Institute (CLSI) TZP breakpoints, failure to update to the current CLSI breakpoints may result in falsely categorizing as many as 20% of the TZP-resistant isolates as susceptible. The impact of not updating clinical breakpoints and strategies for implementation of updated breakpoints are discussed.

Impact of the Recent Clinical and Laboratory Standards Institute Breakpoint Changes on the Antimicrobial Spectrum of Aminoglycosides and the Activity of Plazomicin Against Multidrug-Resistant and Carbapenem-Resistant Enterobacterales From United States Medical Centers.

The Clinical and Laboratory Standards Institute (CLSI) lowered the Enterobacterales-susceptible/-resistant breakpoints for amikacin in 2023 from ≤16/≥64 mg/L to ≤4/≥16 mg/L and the breakpoints for gentamicin and tobramycin from ≤4/≥16 mg/L to ≤2/≥8 mg/L. Because aminoglycosides are frequently used to treat infections caused by multidrug-resistant (MDR) and carbapenem-resistant Enterobacterales (CRE), we evaluated the impact of these changes on the susceptibility rates (%S) of Enterobacterales collected from US medical centers. A total of 9809 Enterobacterales isolates were consecutively collected (1/patient) from 37 US medical centers in 2017-2021 and susceptibility was tested by broth microdilution. Susceptibility rates were calculated using CLSI 2022, CLSI 2023, and US Food and Drug Administration 2022 criteria. Aminoglycoside-nonsusceptible isolates were screened for genes encoding aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methyltransferases (16RMT). The CLSI breakpoint changes mostly affected amikacin, especially against MDR (94.0%S to 71.0%S), extended-spectrum β-lactamase (ESBL)-producing (96.9%S to 79.7%S), and CRE (75.2%S to 59.0%S) isolates. Plazomicin was active against 96.4% of isolates and retained potent activity against CRE (94.0%S), ESBL-producing (98.9%S), and MDR (94.8%S) isolates. Gentamicin and tobramycin showed limited activity against resistant subsets of Enterobacterales. The AME-encoding genes and 16RMT were observed in 801 (8.2%) and 11 (0.1%) isolates, respectively. Plazomicin was active against 97.3% of the AME producers. The spectrum of activity of amikacin against resistant subsets of Enterobacterales was drastically reduced when interpretative criteria based on pharmacokinetic/pharmacodynamic parameters that are currently used to establish breakpoints for other antimicrobials were applied. Plazomicin was markedly more active than amikacin, gentamicin, or tobramycin against antimicrobial-resistant Enterobacterales.

Evaluation of Piperacillin-Tazobactam Testing against Enterobacterales by the Phoenix, MicroScan, and Vitek2 Tests Using Updated Clinical and Laboratory Standards Institute Breakpoints.

In 2022, the Clinical and Laboratory Standards Institute (CLSI) updated piperacillin-tazobactam (TZP) breakpoints for Enterobacterales, based on substantial data suggesting that historical breakpoints did not predict treatment outcomes for TZP. The U.S. Food and Drug Administration (FDA) has not yet adopted these breakpoints, meaning commercial manufacturers of antimicrobial susceptibility testing devices cannot obtain FDA clearance for the revised breakpoints. We evaluated the Phoenix (BD, Sparks, MD), MicroScan (Beckman Coulter, Sacramento, CA), and Vitek2 (bioMérieux, Durham, NC) TZP MICs compared to reference broth microdilution for a collection of 284 Enterobacterales isolates. Phoenix (n = 167 isolates) demonstrated 84.4% categorical agreement (CA), with 4.2% very major errors (VMEs) and 1.8% major errors (MEs) by CLSI breakpoints. In contrast, CA was 85.0% with 4.3% VMEs and 0.8% MEs for the Phoenix with FDA breakpoints. MicroScan (n = 55 isolates) demonstrated 80.0% CA, 36.4% VMEs, and 4.8% MEs by CLSI breakpoints and 81.8% CA, 44.4% VMEs, and 0.0% MEs by FDA breakpoints. Vitek2 (n = 62 isolates) demonstrated 95.2% CA, 6.3% VMEs, and 0.0% MEs by CLSI and 96.8% CA, 0.0% VMEs, and 2.2% MEs by FDA breakpoints. Overall, the performance of the test systems was not substantially different using CLSI breakpoints off-label than using on-label FDA breakpoints. However, limitations were noted with higher-than-desired VME rates (all three systems) and lower-than-desired CA (MicroScan and Phoenix). Laboratories should consider adoption of the revised CLSI breakpoints with automated test systems but be aware that some performance challenges exist for testing TZP on automated systems, regardless of breakpoints applied.

183. Impact of Revised Piperacillin/Tazobactam Clinical Breakpoints on Enterobacterales Isolates Identified in Blood Cultures

Abstract Background Enterobacterales are a significant cause of bloodstream infections (BSI) in hospitalized patients. Prior evidence suggests that treatment with piperacillin/tazobactam may not be ideal for BSI. Piperacillin/tazobactam clinical breakpoints were recently updated by the Clinical and Laboratory Standards Institute (CLSI). Methods We retrospectively evaluated Enterobacterales blood isolates identified by MALDI-TOF (Vitek MS, bioMérieux) between January 1, 2017 through December 31, 2021 at Rush University Medical Center in Chicago, Illinois. Antimicrobial susceptibility testing was performed using NM43 or NM56 panels on the MicroScan WalkAway 96 (Beckman Coulter). The range of dilutions of piperacillin/tazobactam included on both panels was 8/4 to 64/4 μg/mL. Minimal inhibitory concentrations (MIC) were interpreted using current CLSI breakpoints. Results We evaluated 1597 Enterobacterales isolates. Most isolates identified were Escherichia coli [n=806 (50%)] and Klebsiella pneumoniae [n=358 (22%)]. The majority of isolates (90.4%) were susceptible; 28 (1.8%) isolates were susceptible-dose dependent and 125 (7.8%) were resistant to piperacillin/tazobactam using the new CLSI breakpoints (Table). 236 isolates had a multidrug-resistant phenotype, of which 216 (92%) were confirmed as an ESBL. Among ESBL-producing isolates, the majority (81%) were susceptible [MIC ≤ 8 µg/mL) to piperacillin/tazobactam. Isolates with confirmed carbapenemase production had off-scale MICs ( &amp;gt; 64 µg/mL) (Figure). Piperacillin/Tazobactam Breakpoint Revision Table Overall changes in piperacillin/tazobactam interpretations using revised breakpoints. MDR-Enterobacterales piperacillin/tazobactam MIC distributions Piperacillin/tazobactam minimal inhibitory concentration distributions among multidrug-resistant Enterobacterales isolates. Conclusion While there was an increase in resistance, our results indicate that most Enterobacterales isolates tested susceptible to piperacillin/tazobactam using the revised CLSI breakpoints. Disclosures Nicholas M. Moore, PhD, D(ABMM), Abbott Molecular: Grant/Research Support|Cepheid: Grant/Research Support.

Genomic analysis of Fosfomycin resistance in multi-drug resistant uropathogens and comparison of in-vitro susceptibility methods uropathogens.

Urinary tract infection is one of the most common bacterial infections causing high morbidity and mortality. The alarming rise of multidrug-resistant uropathogens worldwide forced the clinician to rethink the old drugs like Fosfomycin for its therapeutic management. Our objective was to compare agar dilution, disc diffusion and E-test method for antimicrobial susceptibility testing of Fosfomycin against different drug-resistant uropathogens. Consecutive 181 uropathogens were tested for Fosfomycin susceptibility using agar dilution, disc diffusion and E-test. Results were interpreted using Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. Whole genome sequencing analysis was done on the 4 XDR/PDR Fosfomycin resistant Klebsiella pneumoniae isolates. Escherichia coli was found as the most common (62.4%) uropathogen followed by Klebsiella pneumoniae (21%). Considering agar dilution as the gold standard, 6.1% of isolates were resistant to Fosfomycin. Following CLSI breakpoints, the susceptibility of Escherichia coli, Klebsiella pneumoniae, other Enterobacterales and Pseudomonas aeruginosa were 92.9%, 92.1%, 100%, 100%; whereas using EUCAST breakpoints the susceptibility rates were 85.7%, 86.9%, 92.9%, and 100%, respectively. The essential agreement, categorical agreement, major error, and very major error for E-test/disc diffusion for all the organisms were 91.2%/Not Applicable, 95%/93.9%, 1.8%/4.7%, 9.1%/9.1%, respectively. Whole-genome sequencing showed mutation UhpT gene as well as the presence of plasmid-mediated fosA5 or fosA6 genes conferring Fosfomycin resistance. This result supports very low resistance of Enterobacterales against Fosfomycin; hence should be considered a valuable option to treat multidrug-resistant uropathogens. Disc diffusion was observed to be a convenient method for Fosfomycin susceptibility testing compared to agar dilution.

Focused Commentary; About Revision of CLSI Antimicrobial Breakpoints, 2018-2021

In recent years, antimicrobial resistance has been on the rise and infectious disease specialists and other clinicians face several challenges when treating patients with antimicrobial resistant infections. Clinical and Laboratory Standards Institute (CLSI) annually publishes guidelines for antimicrobial resistance tests, including revised antimicrobial breakpoints, because of the rise in antimicrobial resistance and changes to nomenclature owing to advances in whole genome sequencing technology. However, many laboratories use historical guidelines and do not follow the revised breakpoints. Moreover, the current breakpoints have limitations. This study evaluated the changes in antimicrobial breakpoints over the last 4 years, from 2018 to 2021. Here, I describe the microbiological and clinical background of the CLSI breakpoint revision and evaluate the advantages and limitations of new breakpoints with a review of large study data. In addition, I reviewed problems associated with each antimicrobial breakpoint and made suggestions for how they might be improved, for example, increasing or decreasing the minimum inhibitory concentration (MIC) or zone diameter, deleting or adding an S, I, or R category, introducing new concepts (such as susceptible-dose dependent (SDD)), and requesting more evaluation methods. Conclusions; CLSI annually publishes guidelines for antimicrobial resistance tests. I reviewed problems associated with each antimicrobial breakpoint for last 4 years, and made suggestions for how they might be improved.

Antimicrobial susceptibility testing of clinical isolates of Gram-negative bacilli collected in Morocco by the ATLAS Global Surveillance Program from 2018 to 2020

To report reference method antimicrobial susceptibility testing results for recent clinical isolates of Gram-negative bacilli from Morocco. CLSI (Clinical and Laboratory Standards Institute) broth microdilution antimicrobial susceptibility testing was performed by a central laboratory for isolates of Enterobacterales (n=810), Pseudomonas aeruginosa (n=321), and Acinetobacter baumannii (n=191) collected in 2018-2020 by three hospital laboratories in Morocco. MICs were interpreted using both CLSI (2021) and EUCAST (European Committee on Antimicrobial Susceptibility Testing) (2021) breakpoints. Molecular testing for β-lactamase genes was performed on isolates meeting defined screening criteria. Most isolates of Enterobacterales were susceptible (CLSI/EUCAST breakpoints) to amikacin (98.0%/96.2%), ceftazidime-avibactam (94.8%/94.8%), and meropenem (92.5%/94.2%). Of Enterobacterales isolates eligible for β-lactamase gene screening (n=210), 174 were ESBL-positive, 40 were metallo-β-lactamase-positive (all NDM), 39 were serine carbapenemase-positive (all OXA); and 7 isolates carried both OXA-48 and NDM-1. Amikacin (89.1%/89.1%) and ceftazidime-avibactam (88.2%/88.2%) were the most active agents tested against P. aeruginosa. Applying CLSI and EUCAST breakpoints, MDR rates were 21.9% and 29.3% for Enterobacterales and 18.4% and 21.8% for P. aeruginosa. Susceptible rates for amikacin, ceftazidime-avibactam, and meropenem were 93.2%/89.5%, 77.4%/82.3%, and 67.8%/80.2% for MDR Enterobacterales and 50.8%/57.1%, 40.7%/45.7%, and 27.1/32.9% for MDR P. aeruginosa. ≥70% of A. baumannii isolates were resistant to all agents tested (except colistin, EUCAST breakpoints only) including amikacin and meropenem. Newer β-lactam/β-lactamase inhibitor combinations such as ceftazidime-avibactam warrant testing and reporting for Enterobacterales and P. aeruginosa in Morocco given the presence of significant resistance to first-line β-lactams and fluoroquinolones, pervasive ESBLs and carbapenemases, and toxicity concerns associated with some second-line agents.

Clinical effectiveness of beta-lactams versus fluoroquinolones as empirical therapy in patients with diabetes mellitus hospitalized for urinary tract infections: A retrospective cohort study.

BackgroundDiabetic patients are at risk of severe urinary tract infections (UTIs). Due to the emerging resistance rates to fluoroquinolones and β-lactams, we aimed to evaluate the effectiveness of β-lactams versus fluoroquinolones as empirical therapy for diabetic patients hospitalized for UTIs.MethodsA retrospective cohort study was conducted in a medical center in Taiwan between 2016 and 2018. Patients with type 2 diabetes, aged ≥20 and hospitalized for UTIs were enrolled. Patients with UTI diagnosis within one year before the admission, co-infections at the admission, or ≥2 pathogens in the urine cultures were excluded. The primary outcome was empiric treatment failure.Results298 patients were followed for at least 30 days after the admission. Escherichia coli (61.07%) was the most common pathogen. The resistance rates of the pathogens to levofloxacin were 28.52% and 34.22% according to the historical Clinical and Laboratory Standards Institute (CLSI) breakpoints and the updated 2019 CLSI breakpoints, respectively. The resistance rates of ceftazidime and cefepime were 21.81% and 11.41%, respectively. Empirical β-lactams were associated with less treatment failure compared to fluoroquinolones (adjusted OR = 0.32, 95% CI = 0.17–0.60). Beta-lactams were associated with less treatment failure than fluoroquinolones when appropriatness was determined by the pre-2019 CLSI breakpoints but not the 2019 CLSI breakpoints.ConclusionsIn diabetic patients hospitalized for UTIs, β-lactams were associated with less empiric treatment failure compared to fluoroquinolones when the resistance rate to fluoroquinolone is higher than β-lactams. The updated 2019 CLSI breakpoint for fluoroquinolone was better than pre-2019 CLSI breakpoints to correlate with treatment outcomes for hospitalized UTIs in diabetic patients.

Surveillance of Fluoroquinolone Resistance in Wisconsin: Geographic Variation and Impact of Revised CLSI Breakpoints

Objective: Many clinical microbiology laboratories procure antimicrobial susceptibility testing data using guidelines established by Clinical and Laboratory Standards Institute (CLSI). When necessary, CLSI revises interpretive breakpoints in efforts to improve clinical correlation, with two revisions relative to fluoroquinolone agents occurring in 2019. The purpose of this investigation was to determine the impact of fluoroquinolone breakpoint revisions on Wisconsin clinical isolates of Escherichia coli, Proteus mirabilis, and Pseudomonas aeruginosa. Design: Multi-center laboratory surveillance, with testing at a single location utilizing standardized media and susceptibility testing protocols.Methods: From the Surveillance of Wisconsin Organisms for Trends in Antimicrobial Resistance and Epidemiology (SWOTARE) program, levofloxacin and ciprofloxacin minimum inhibitory concentration (MIC) values for 1911, 1521, and 1463 Wisconsin isolates of E. coli, P. mirabilis, and P. aeruginosa, respectively, were determined by broth microdilution testing. In separate data analyses, all MIC data were interpreted using CLSI breakpoints published prior to 2019, then secondarily by using CLSI breakpoints published since 2019 (which reflect lower breakpoints for both levofloxacin and ciprofloxacin resistance). Findings were further stratified by Wisconsin Department of Health Services region.Results: Up to 3.2% decreased statewide fluoroquinolone susceptibility was observed for E. coli isolates, while 5.1% and 6.3% decreases in levofloxacin susceptibility were noted for P. aeruginosa and P. mirabilis isolates, respectively, when revised breakpoints were applied. E. coli isolates from the Western region and P. mirabilis isolates from the Southeastern region demonstrated significant shifts toward decreased fluoroquinolone susceptibility upon application of revised breakpoints. Northern region P. mirabilis isolates exhibited consistently decreased fluoroquinolone susceptibility.Conclusions: Fluoroquinolone resistance has been underreported in Wisconsin as a whole, yet geographic variability continues to exist. Targeted annual surveillance is important to identify and monitor resistance trending. Compilations of SWOTARE surveillance data can be utilized to predict the impact of future CLSI interpretive breakpoint revisions in Wisconsin.

Setting Antimicrobial Susceptibility Testing Breakpoints: A Primer for Pediatric Infectious Diseases Specialists on the Clinical and Laboratory Standards Institute Approach.

Breakpoints are the values used by clinical microbiology laboratories to interpret the results of antimicrobial susceptibility testing (AST) and classify isolates as susceptible or resistant. Whether the breakpoints applied by laboratories accurately predict the likelihood of successful treatment with a particular antimicrobial is an issue of critical importance to quality clinical care. In the United States, the Food and Drug Administration (FDA) sets breakpoints, and globally, breakpoints are also set by 2 standards development organizations, the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST); individual laboratories may choose which breakpoints to implement. Many CLSI breakpoints are recognized by FDA, facilitating their incorporation into widely used commercial AST devices. The CLSI Subcommittee on AST's consensus approach to establishing (and as needed, revising) breakpoints involves integration of currently available microbiological, pharmacokinetic-pharmacodynamic, and clinical data. Here, an overview of the CLSI process for establishing breakpoints is provided.

1256. Clinical Response by Minimum Inhibitory Concentrations in Carbapenem-Resistant Pseudomonas aeruginosa Infections under Cefiderocol Compassionate Use Program

BackgroundCefiderocol (CFDC) has been developed for the treatment of serious infections caused by drug-resistant aerobic Gram-negative pathogens, including carbapenem-resistant (CR) Pseudomonas aeruginosa (CRPA). The current CFDC susceptibility breakpoints for P. aeruginosa differ between US Food and Drug Administration (FDA) and Clinical and Laboratory Standards Institute (CLSI) (Table). Data characterizing the impact of CFDC minimum inhibitory concentrations (MICs) on the clinical responses of patients treated with CFDC for CRPA are sparse.MethodsWe reviewed patients treated with compassionate-use CFDC (2 g, q8h or renally adjusted dosages) for infections caused by CRPA with no alternative treatment options. CFDC minimum inhibitory concentrations (MICs) were evaluated according to CLSI guidelines in iron-depleted cation-adjusted Müller–Hinton broth for available CRPA isolates. We then assessed physician-reported clinical responses to CFDC therapy and stratified results by CFDC MIC. ResultsThere were 71 patients overall with CRPA treated with CFDC. Treatment duration ranged from 1 to 132 days. For the subset of 33 patients for whom CFDC MIC values were available, the most common infection sites were the respiratory tract (n=15), blood (n=12), and urinary tract (n=4). Patients could have had an infection at ≥1 sites and in other locations. CFDC MIC range was ≤0.03– >64 µg/mL. The modal MIC value was 2 µg/mL (n=13; Table). CRPA isolates were susceptible to CFDC in 13/33 patients (39.4%) based on the FDA breakpoint (MIC ≤1 µg/mL) and in 31/33 patients (93.9%) based on the CLSI breakpoint (MIC ≤4 µg/mL). Clinical response was reported for 15/18 patients (83.3%) who had infections with CFDC MICs of 2–4 µg/mL, organisms that are considered susceptible by CLSI but not by FDA breakpoints (Table). Clinical response was reported in 6/13 patients (46.1%) with infections with CFDC MIC ≤1 µg/mL and in 1 of 2 patients (50.0%) with CFDC MIC ≥8 µg/mL (Table). 21 (63.6%) patients survived to Day 28 and there were no trends in mortality by CFDC MIC. ConclusionClinical response rate was high for CRPA infections with CFDC MICs of 2–4 µg/mL, supporting the higher CLSI susceptibility breakpoint.Disclosures Michael J. Satlin, MD, MS, Achaogen (Consultant)Allergan (Research Grant or Support)BioFire Diagnostics (Research Grant or Support)Merck (Research Grant or Support)Shionogi (Consultant) David Fam, PharmD, Shionogi (Employee) Roger Echols, MD, Shionogi (Consultant) Christopher Longshaw, PhD, Shionogi (Employee) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Yoshinori Yamano, PhD, Shionogi (Employee)

1220. Is MIC all that matters? MIC Distributions of Ceftazidime and Cefepime in Ceftriaxone-Resistant E. coli and Klebsiella spp

BackgroundThe Clinical and Laboratory Standards Institute (CLSI) lowered MIC breakpoints for many beta-lactam antibiotics to enhance detection of resistance among Enterobacterales. This shift was also meant to eliminate the need for routine testing for extended-spectrum beta-lactamases (ESBLs). The recommended treatment for ESBL-producing Enterobacterales is carbapenems. The IDSA guidelines for MDR-GN organisms recommend using ceftriaxone (CRO) resistance as a proxy for ESBL production and thus carbapenem treatment. Under CLSI guidelines, alternative beta-lactams such as ceftazidime (CAZ) and cefepime (FEP) may still be reported as susceptible and thus used by clinicians even in light of IDSA recommendations. The aim of this project was to characterize the MIC distributions of CAZ and FEP stratified by CRO susceptibility.MethodsClinical E. coli, K. pneumoniae, and K. oxytoca isolates from blood cultures in adult patients from Nov 2016-Dec 2018 that had MICs tested by the Vitek-2 automated susceptibility testing system for CRO, FEP and CAZ were identified. Descriptive statistics were used to compare MIC distributions across the antibiotics of interest (SPSS).Results573 isolates were included, of these, 17.3% were CRO resistant. Most (53%) CRO-R isolates had FEP MICs ≤2 which is considered susceptible per CLSI; 19% had FEP MICs of 4-8 which would be considered S-DD by CLSI (Figure 1A; breakpoints noted by dashed lines). Using the EUCAST breakpoint of ≤1, only 11% of CRO-R isolates would be reported as FEP-S. For CAZ, 40% of CRO-R isolates had CAZ MICs ≤4, which is considered S by CLSI. Using the EUCAST breakpoint of ≤1, only 12% of CRO-R isolates would be reported as CAZ-S (Figure 1B). Cefepime MIC Distribution for Ceftriaxone Resistant Isolates Distribution of MICs for cefepime for ceftriaxone resistant isolates with the breakpoints for EUCAST and CLSI noted with a dashed lineCeftazidime MIC Distribution for Ceftriaxone Resistant Isolates Distribution of MICs for ceftazidime for ceftriaxone resistant isolates with the breakpoints for EUCAST and CLSI noted with a dashed lineConclusionHalf of CRO-R E. coli, K. pneumoniae and K. oxytoca have FEP and CAZ MICs at or below the current CLSI breakpoints. This may lead to their use for serious ESBL infections where a carbapenem is preferred. To prevent unnecessary use, laboratories should consider suppressing FEP and CAZ susceptibilities when CRO-R or adopting more the aggressive EUCAST breakpoints for these agents. Disclosures Emily Heil, PharmD, MS, BCIDP, Nothing to disclose Kimberly C. Claeys, PharmD, GenMark (Speaker’s Bureau)

Ceftolozane-tazobactam activity against clinical isolates of Pseudomonas aeruginosa from ICU patients with pneumonia: United States, 2015–2018

To report on the activity of ceftolozane-tazobactam and comparators against Pseudomonas aeruginosa isolates collected from hospitalized patients with pneumonia in US intensive care units (ICUs) between 2015 and 2018. Activity against all P. aeruginosa and common resistant phenotypes are described to better inform decision-making and support antimicrobial stewardship efforts. In total, 781 P. aeruginosa isolates were collected from 28 US hospitals. These isolates were tested for susceptibility to ceftolozane-tazobactam and comparators by Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology using CLSI (2020) breakpoints. Phenotypes analysed included piperacillin-tazobactam-non-susceptible (NS), cefepime-NS, ceftazidime-NS, meropenem-NS and difficult-to-treat resistance (DTR). Ceftolozane-tazobactam was the most potent agent tested (minimum inhibitory concentration to inhibit 50% and 90% of isolates of 0.5 and 2 mg/L, respectively, inhibiting 97.2% at the susceptible breakpoint of ≤4 mg/L). Traditional first-line antipseudomonal β-lactam antibiotics (piperacillin-tazobactam, cefepime and ceftazidime) demonstrated <33% susceptibility when P. aeruginosa was NS to one or more agent. Although escalation of therapy to meropenem is commonly employed clinically, meropenem susceptibility ranged from 33.6% to 44.9% if P. aeruginosa was NS to any traditional first-line antipseudomonal β-lactam agent. Conversely, ceftolozane-tazobactam remained active against isolates that were NS to other agents, inhibiting 88.4% of isolates NS to piperacillin-tazobactam, 85.0% of isolates NS to cefepime and ceftazidime, and 90.3% of isolates NS to meropenem. Ceftolozane-tazobactam also maintained activity against 73.0% of DTR isolates. Ceftolozane-tazobactam maintained high activity against P. aeruginosa isolated from hospitalized patients with pneumonia in US ICUs, and had the greatest activity against isolates NS to one or more antipseudomonal β-lactams and DTR isolates.

Susceptibility to Imipenem/Relebactam of Pseudomonas aeruginosa and Acinetobacter baumannii Isolates from Chinese Intra-Abdominal, Respiratory and Urinary Tract Infections: SMART 2015 to 2018.

PurposeIn recent years, less options are available for treating carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Pseudomonas aeruginosa. The present study investigates the susceptibility rates to imipenem/relebactam for the treatment of intra-abdominal infections (IAIs), respiratory tract infections (RTIs) and urinary tract infections (UTIs) caused by A. baumannii and P. aeruginosa in China.Patients and MethodsA total of 1886 P. aeruginosa and 1889 A. baumannii isolates were collected in 21 centers (7 regions) as a part of the global SMART surveillance program between 2015 and 2018. Antimicrobial susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) recommendations using the broth microdilution methodology at Peking Union Medical College Hospital.ResultsFor P. aeruginosa, overall susceptibility rates to imipenem/relebactam were 84.2% at a CLSI breakpoint of ≤2 mg/L compared to 55.7% for imipenem. Susceptibility rates of imipenem-non-susceptible P. aeruginosa to imipenem/relebactam were 64.4% and for multidrug-resistance (MDR) P. aeruginosa susceptibility rates were increased from 25.2% for imipenem to 65.8% for imipenem/relebactam. The susceptibilities of imipenem-non-susceptible and MDR P. aeruginosa strains were similarly restored by imipenem/relebactam in non-ICU and ICU wards. The rate of imipenem-non-susceptibilities A. baumannii isolates was 79.0%, whereas the MDR rate was 81.9%. Relebactam did not change the susceptibilities of imipenem-non susceptible or MDR A. baumannii isolates.ConclusionImipenem/relebactam provides a therapy option to treat infections caused by MDR or imipenem-non-susceptible P. aeruginosa but not A. baumannii infections in China.