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.

Cefazolin as a predictor of urinary cephalosporin activity in indicated Enterobacterales.

Traditionally, cephalothin susceptibility results were used to predict the susceptibility of additional cephalosporins; however, in 2013-2014, the Clinical and Laboratory Standards Institute (CLSI) revisited this practice and determined that cefazolin is a more accurate proxy than cephalothin for uncomplicated urinary tract infections (uUTIs). Therefore, a cefazolin surrogacy breakpoint was established to predict the susceptibility of seven oral cephalosporins for Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis in the context of uUTIs. Clinical microbiology laboratories face several operational challenges when implementing the cefazolin surrogacy breakpoint, which may lead to confusion for the best path forward. Here, we review the historical context and data behind the surrogacy breakpoints, review PK/PD profiles for oral cephalosporins, discuss challenges in deploying the breakpoint, and highlight the limited clinical outcome data in this space.

A multi-species outbreak of VIM-producing carbapenem-resistant bacteria in a burn unit and subsequent investigation of rapid development of cefiderocol resistance.

Carbapenem resistance due to metallo-ß-lactamases (MBLs) such as the Verona integron-encoded metallo-ß-lactamase (VIM) is particularly problematic due to the limited treatment options. We describe a case series of bacterial infections in a tertiary care hospital due to multi-species acquisition of a VIM gene along with our experience using novel ß-lactam antibiotics and antibiotic combinations to treat these infections. Four patients were treated with the combination of ceftazidime-avibactam and aztreonam, with no resistance to the combination detected. However, cefiderocol-resistant Klebsiella pneumoniae isolates were detected in two out of the five patients who received cefiderocol within 3 weeks of having started the antibiotic. Strain pairs of sequential susceptible and resistant isolates from both patients were analyzed using whole-genome sequencing. This analysis revealed that the pairs of isolates independently acquired point mutations in both the cirA and fiu genes, which encode siderophore receptors. These point mutations were remade in a laboratory strain of K. pneumoniae and resulted in a significant increase in the MIC of cefiderocol, even in the absence of a beta-lactamase enzyme or a penicillin-binding protein 3 (PBP3) mutation. While newer ß-lactam antibiotics remain an exciting addition to the antibiotic armamentarium, their use must be accompanied by diligent monitoring for the rapid development of resistance.

Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections.

BACKGROUND: The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant infections. This guidance document focuses on infections caused by extended-spectrum ß-lactamase producing Enterobacterales (ESBL-E), AmpC ß-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia. This updated document replaces previous versions of the guidance document. METHODS: A panel of six infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated questions about the treatment of infections caused by ESBL-E, AmpC-E, CRE, DTR-P. aeruginosa, CRAB, and S. maltophilia. Because of differences in the epidemiology of resistance and availability of specific anti-infectives internationally, this document focuses on the treatment of infections in the United States. RESULTS: Preferred and alternative suggested treatment approaches are provided with accompanying rationales, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, transitioning to oral therapy, duration of therapy, and other management considerations are also discussed briefly. Suggested approaches apply for both adult and pediatric populations, although suggested antibiotic dosages are provided only for adults. CONCLUSIONS: The field of antimicrobial resistance is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of antimicrobial resistant infections. This document is current as of December 31, 2022 and will be updated periodically. The most current version of this document, including date of publication, is available at www.idsociety.org/practice-guideline/amr-guidance/.

Successful Treatment of Persistent Stenotrophomonas maltophilia Bacteremia With Cefiderocol in an Infant.

Stenotrophomonas maltophilia is an important nosocomial pathogen with limited treatment options. Trimethoprim-sulfamethoxazole (TMP-SMX) is generally regarded as the preferred therapy; however, treatment failures with TMP-SMX have been reported. Herein, we report a case of a 5-week-old infant with 8 days of S. maltophilia bacteremia while receiving TMP-SMX, despite in vitro susceptibility. Transitioning to cefiderocol monotherapy resulted in blood culture clearance within 24 hours, in the absence of any additional interventions. This is the first published case of the use of cefiderocol for a pediatric patient with an infection due to S. maltophilia. We review preclinical and clinical data that underscore why cefiderocol may be an effective treatment option for S. maltophilia infections.

Fosfomycin Disk Diffusion Testing among Klebsiella pneumoniae Results in Frequent Inner Colonies and Categorical Disagreement Based on Conflicting Breakpoint Organization Recommendations.

Recent studies indicate that discrete inner colonies (ICs) arise during fosfomycin disk diffusion (DD) testing. CLSI and EUCAST have contradicting recommendations on the interpretation of ICs; CLSI recommends considering them while EUCAST recommends ignoring them when interpreting DD results. We sought to compare the categorical agreement of DD and agar dilution (AD) MIC and to assess the implications of ICs interpretation on zone diameter readings. A convenience sample of 80 Klebsiella pneumoniae clinical isolates with varied phenotypic profiles collected from 3 United States locations was included. Susceptibility was determined in duplicate, using both organization recommendations and interpretations for Enterobacterales. Correlations between methods were calculated using EUCASTIV AD as the reference method. MIC values ranged from 1 to >256 µg/mL with an MIC50/90 of 32/256 µg/mL. Extrapolating EUCASToral and CLSI AD Escherichia coli breakpoints, 12.5% and 83.8% of isolates were susceptible, respectively, whereas 66.3% were susceptible by EUCASTIV AD-which applies to K. pneumoniae. CLSI DD measurements were 2 to 13 mm smaller than EUCAST measurements due to 66 (82.5%) isolates producing discrete ICs. Categorical agreement with EUCASTIV AD was greatest for CLSI AD (65.0%) and poorest for EUCASToral DD (6.3%). Isolates among this collection were frequently classified into different interpretive categories based on varying breakpoint organization recommendations. The more conservative oral breakpoints of EUCAST resulted in more isolates categorized as resistant despite frequent ICs. Differing zone diameter distributions and poor categorical agreement highlight issues of extrapolating E. coli breakpoints and methods to other Enterobacterales, and the clinical relevance of this issue warrants further investigation. IMPORTANCE Fosfomycin susceptibility testing recommendations are complex. Both the Clinical and Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recognize agar dilution as the reference method, but they also support disk diffusion as an approved method for Escherichia coli. However, these two organizations have conflicting recommendations for the interpretation of inner colonies that arise during disk diffusion testing which can lead to varying zone diameters and interpretations despite isolates having identical MIC values. Using a collection of 80 Klebsiella pneumoniae isolates, we found that a large (82.5%) portion produced discrete inner colonies during disk diffusion and isolates were frequently classified into different interpretive categories. The more conservative breakpoints of EUCAST resulted in more isolates categorized as resistant despite frequent inner colonies. Differing zone diameter distributions and poor categorical agreement highlight issues of extrapolating E. coli breakpoints and methods to other Enterobacterales, and the clinical relevance of this issue warrants further investigation.

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.

Consecutive antibiotic shortages highlight discrepancies between microbiology and prescribing practices for intra-abdominal infections.

Piperacillin-tazobactam (TZP) is frequently used for intra-abdominal infection (IAI). Our institution experienced consecutive shortages of TZP and cefepime, providing an opportunity to review prescribing patterns and microbiology for IAI. Hospitalized adult patients treated for IAI, based on provider selection of IAI as the indication within the antibiotic order, between March 2014 and February 2018 were identified from the University of Virginia Clinical Data Repository and Infection Prevention and Control Database. Antimicrobial utilization, microbiologic data, and clinical outcomes were compared across four year-long periods: pre-shortage, TZP shortage, cefepime shortage, and post-shortage. There were 7,668 episodes of antimicrobial prescribing for an indication of IAI during the study period. Cefepime use for IAI increased 190% during the TZP shortage; meanwhile ceftriaxone use increased by only 57%. There was no increase in in-house mortality, colonization with resistant organisms, or Clostridiodes difficile infection among patients treated with IAI during the shortage periods. Among a subset of cases randomly selected for review, Pseudomonas sp. was a rare cause of IAI, but anti-pseudomonal antibiotics were commonly prescribed empirically. We observed a large increase in cefepime utilization for IAI during a TZP shortage that was not warranted based on the observed frequency of identification of Pseudomonas sp. as the causative organism in IAI, suggesting a need to revisit national guideline recommendations.

Breaking Down the Breakpoints: Rationale for the 2022 Clinical and Laboratory Standards Institute Revised Piperacillin-Tazobactam Breakpoints Against Enterobacterales.

Piperacillin-tazobactam (PTZ) is one of the most common antibiotics administered to hospitalized patients. Its broad activity against gram-negative, gram-positive, and anaerobic pathogens; efficacy in clinical trials across diverse infection types and patient populations; and generally favorable toxicity profile make it a particularly appealing antibiotic agent. PTZ susceptibility interpretive criteria (ie, breakpoints) for the Enterobacterales were initially established in 1992, as the drug was undergoing approval by the US Food and Drug Administration. In the ensuing 30 years, changes in the molecular epidemiology of the Enterobacterales and its impact on PTZ susceptibility testing, mounting pharmacokinetic/pharmacodynamic data generated from sophisticated techniques such as population pharmacokinetic modeling and Monte Carlo simulation, and disturbing safety signals in a large clinical trial prompted the Clinical Laboratory and Standards Institute (CLSI) to review available evidence to determine the need for revision of the PTZ breakpoints for Enterobacterales. After an extensive literature review and formal voting process, the susceptibility criteria were revised in the 2022 CLSI M100 document to the following: ≤8/4 µg/mL (susceptible), 16/4 µg/mL (susceptible dose-dependent), and ≥32/4 µg/mL (resistant). Herein, we provide a brief overview of the CLSI process of antibiotic breakpoint revisions and elaborate on the available data that ultimately led to the decision to revise the PTZ breakpoints.

Outbreak of Burkholderia stabilis Infections Associated with Contaminated Nonsterile, Multiuse Ultrasound Gel - 10 States, May-September 2021.

In July 2021, the Virginia Department of Health notified CDC of a cluster of eight invasive infections with Burkholderia stabilis, a bacterium in the Burkholderia cepacia complex (BCC), among hospitalized patients at hospital A. Most patients had undergone ultrasound-guided procedures during their admission. Culture of MediChoice M500812 nonsterile ultrasound gel used in hospital A revealed contamination of unopened product with B. stabilis that matched the whole genome sequencing (WGS) of B. stabilis strains found among patients. CDC and hospital A, in collaboration with partner health care facilities, state and local health departments, and the Food and Drug Administration (FDA), identified 119 B. stabilis infections in 10 U.S. states, leading to the national recall of all ultrasound gel products produced by Eco-Med Pharmaceutical (Eco-Med), the manufacturer of MediChoice M500812. Additional investigation of health care facility practices revealed frequent use of nonsterile ultrasound gel to assist with visualization in preparation for or during invasive, percutaneous procedures (e.g., intravenous catheter insertion). This practice could have allowed introduction of contaminated ultrasound gel into sterile body sites when gel and associated viable bacteria were not completely removed from skin, leading to invasive infections. This outbreak highlights the importance of appropriate use of ultrasound gel within health care settings to help prevent patient infections, including the use of only sterile, single-use ultrasound gel for ultrasonography when subsequent percutaneous procedures might be performed.

Reducing Repeat Blood Cultures in Febrile Neutropenia: A Single-Center Experience.

Background: Limited data exist to guide blood culture ordering in persistent febrile neutropenia (FN), resulting in substantial variation in practice. Unnecessary repeat blood cultures have been associated with patient harm including increased antimicrobial exposure, hospital length of stay, catheter removal, and overall cost. Methods: We conducted a single-center study of adult hematology-oncology patients with ≥3 days of FN. The yield of blood cultures was first evaluated in a 2-year historical cohort. Additionally, a pilot pre-/postintervention study was performed in non-stem cell transplant (SCT) patients following a change in our population clinical practice guideline from a recommendation of daily blood cultures to a clinically guided approach. The primary outcome was cultures collected per days of FN after day 3 of persistent FN. Results: One hundred forty-six episodes of ≥3 days of FN in 108 patients were identified during the historical period. Day 1 blood cultures were positive in 23 of 146 (16%) episodes. Blood cultures were drawn on 374 of 513 (73%) subsequent episode-days (day 2-12) and were negative in 366 of 374 (98%). After the intervention, a 53% decrease was observed in the rate of total blood cultures collected (1.4 preintervention vs 0.7 postintervention; P = .03). Blood cultures obtained after 48 hours rarely yielded clinically significant organisms. Conclusions: Repeat blood cultures are low-yield in persistent FN without new clinical change. A pilot intervention in non-SCT patients successfully reduced the frequency of blood culture collection.

Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019: A Phase 2a Trial.

Background: Based on studies implicating the type 2 cytokine interleukin 13 (IL-13) as a potential contributor to critical coronavirus disease 2019 (COVID-19), this trial was designed as an early phase 2 study to assess dupilumab, a monoclonal antibody that blocks IL-13 and interleukin 4 signaling, for treatment of inpatients with COVID-19. Methods: We conducted a phase 2a randomized, double-blind, placebo-controlled trial (NCT04920916) to assess the safety and efficacy of dupilumab plus standard of care vs placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Results: Forty eligible subjects were enrolled from June to November of 2021. There was no statistically significant difference in adverse events nor in the primary endpoint of ventilator-free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, there were 2 deaths in the dupilumab group compared with 5 deaths in the placebo group (60-day survival: 89.5% vs 76.2%; adjusted hazard ratio [HR], 0.05 [95% confidence interval {CI}, .004-.72]; P = .03). Among subjects who were not in the intensive care unit (ICU) at randomization, 3 subjects in the dupilumab arm were admitted to the ICU compared to 6 in the placebo arm (17.7% vs 37.5%; adjusted HR, 0.44 [95% CI, .09-2.09]; P = .30). Last, we found evidence of type 2 signaling blockade in the dupilumab group through analysis of immune biomarkers over time. Conclusions: Although the primary outcome of day 28 ventilator-free survival was not reached, adverse events were not observed and survival was higher in the dupilumab group by day 60. Clinical Trials Registration: NCT04920916.

Clinical challenges treating Stenotrophomonas maltophilia infections: an update.

Stenotrophomonas maltophilia is a non-fermenting, Gram-negative bacillus that has emerged as an opportunistic nosocomial pathogen. Its intrinsic multidrug resistance makes treating infections caused by S. maltophilia a great clinical challenge. Clinical management is further complicated by its molecular heterogeneity that is reflected in the uneven distribution of antibiotic resistance and virulence determinants among different strains, the shortcomings of available antimicrobial susceptibility tests and the lack of standardized breakpoints for the handful of antibiotics with in vitro activity against this microorganism. Herein, we provide an update on the most recent literature concerning these issues, emphasizing the impact they have on clinical management of S. maltophilia infections.

Infectious Diseases Society of America 2022 Guidance on the Treatment of Extended-Spectrum ß-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa).

BACKGROUND: The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant infections. The initial guidance document on infections caused by extended-spectrum ß-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa) was published on 17 September 2020. Over the past year, there have been a number of important publications furthering our understanding of the management of ESBL-E, CRE, and DTR-P. aeruginosa infections, prompting a rereview of the literature and this updated guidance document. METHODS: A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections reviewed, updated, and expanded previously developed questions and recommendations about the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Because of differences in the epidemiology of resistance and availability of specific anti-infectives internationally, this document focuses on the treatment of infections in the United States. RESULTS: Preferred and alternative treatment recommendations are provided with accompanying rationales, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, duration of therapy, and other management considerations are also discussed briefly. Recommendations apply for both adult and pediatric populations. CONCLUSIONS: The field of antimicrobial resistance is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of antimicrobial-resistant infections. This document is current as of 24 October 2021. The most current versions of IDSA documents, including dates of publication, are available at www.idsociety.org/practice-guideline/amr-guidance/.