Assessing the impact of meropenem exposure on ceftolozane/tazobactam-resistance development in Pseudomonas aeruginosa using in vitro serial passage.

BACKGROUND: Patients infected with difficult-to-treat Pseudomonas aeruginosa are likely to receive meropenem (MEM) empirically before escalation to ceftolozane/tazobactam (C/T). We assessed whether pre-exposure to MEM affected C/T resistance development on C/T exposure. MATERIALS AND METHODS: Nine clinical P. aeruginosa isolates were exposed to MEM 16 mg/L for 72 h. Then, isolates were serially passaged in the presence of C/T (concentration of 10 mg/L) for 72 h as two groups: an MEM-exposed group inoculated with MEM pre-exposed isolates and a non-MEM control group. At 24 h intervals, samples were plated on drug-free and drug-containing agar (C/T concentration 16/8 mg/L) and incubated to quantify bacterial densities (log10 cfu/mL). Growth on C/T agar indicated resistance development, and resistant population was calculated by dividing the cfu/mL on C/T plates by the cfu/mL on drug-free agar. RESULTS: At 72 h, resistant populations were detected in 6/9 isolates. In five isolates, MEM exposure significantly increased the prevalence of ceftolozane/tazobactam-resistance development; the percentages of resistance population were 100%, 100%, 53.5%, 31% and 3% for the MEM-exposed versus 0%, 0%, 2%, 0.35% and ≤0.0003% in the unexposed groups. One isolate had a similar resistant population at 72 h between the two groups. The remaining isolates showed no development of resistance, regardless of previous MEM exposure. CONCLUSIONS: MEM exposure may pre-dispose to C/T resistance development and thus limit the therapeutic utility of this ß-lactam/ß-lactamase inhibitor. Resistance may be a result of stress exposure or molecular-level mutations conferring cross-resistance. Further in vivo studies are needed to assess clinical implications of these findings.

Successful Treatment of Carbapenem-Resistant Acinetobacter baumannii Meningitis with Sulbactam-Durlobactam.

BACKGROUND: The treatment of carbapenem-resistant Acinetobacter baumannii/calcoaceticus complex (CRAB) presents significant treatment challenges. METHODS: We report the case of a 42-year-old woman with CRAB meningitis who experienced persistently positive cerebrospinal fluid (CSF) cultures for 13 days despite treatment with high-dose ampicillin-sulbactam and cefiderocol. On day 13, she was transitioned to sulbactam-durlobactam and meropenem; four subsequent CSF cultures remained negative. After 14 days of sulbactam-durlobactam, she was cured of infection. Whole genome sequencing investigations identified putative mechanisms that contributed to reduced cefiderocol susceptibility observed during cefiderocol therapy. Blood and CSF samples were collected pre-dose and 3-hours post initiation of a sulbactam-durlobactam infusion. RESULTS: The CRAB isolate belonged to sequence type 2. An acquired blaOXA-23 and an intrinsic blaOXA-51-like (i.e., blaOXA-66) carbapenemase gene were identified. The paradoxical effect (i.e., no growth at lower cefiderocol dilutions but growth at higher dilutions) was observed by broth microdilution after 8 days of cefiderocol exposure but not by disk diffusion. Potential markers of resistance to cefiderocol included mutations in the start codon of piuA and piuC iron transport genes and a A515V substitution in PBP3, the primary target of cefiderocol. Sulbactam and durlobactam were detected in CSF at both timepoints, indicating CSF penetration. CONCLUSIONS: This case describes successful treatment of refractory CRAB meningitis with the administration of sulbactam-durlobactam and meropenem and highlights the need to be cognizant of the paradoxical effect that can be observed with broth microdilution testing of CRAB isolates with cefiderocol.

A multi-center validation of the electronic health record admission source and discharge location fields against the clinical notes for identifying inpatients with long-term care facility exposure.

Identifying long-term care facility (LTCF)-exposed inpatients is important for infection control research and practice, but ascertaining LTCF exposure is challenging. Across a large validation study, electronic health record data fields identified 76% of LTCF-exposed patients compared to manual chart review. OBJECTIVE: Residence or recent stay in a long-term care facility (LTCF) is an important risk factor for antibiotic-resistant bacterial colonization. However, absent dedicated intake questionnaires or resource-intensive chart review, ascertaining LTCF exposure in inpatients is challenging. We aimed to validate the electronic health record (EHR) admission and discharge location fields against the clinical notes for identifying LTCF-exposed inpatients. METHODS: We conducted a retrospective study of 1020 randomly sampled adult admissions between 2016 and 2021 across 12 University of Maryland Medical System hospitals. Using study-developed guidelines, we categorized the following data for LTCF exposure: each admission's history & physical (H&P) note, each admission's EHR-extracted "Admission Source," and (3) the EHR-extracted admission and discharge locations for previous admissions (≤90 days). We estimated sensitivities, with 95% CIs, of H&P notes and of EHR admission/discharge location fields for detecting "current" and "any recent" (≤90 days, including current) LTCF exposure. RESULTS: For detecting current LTCF exposure, the sensitivity of the index admission's EHR-extracted "Admission Source" was 46% (95% CI: 35%­58%) and of the H&P note was 92% (83%­97%). For detecting any recent LTCF exposure, the sensitivity of "Admission Source" across the index and previous admissions was 32% (24%­41%), "Discharge Location" across previous admission(s) was 57% (47%­66%), and of the H&P note was 68% (59%­76%). The combined sensitivity of admission source and discharge location for detecting any recent LTCF exposure was 76% (67%­83%). CONCLUSIONS: The EHR-obtained admission source and discharge location fields identified 76% of LTCF-exposed patients compared to chart review but disproportionately missed currently exposed patients.

Understanding the role of antibiotic-associated adverse events in influencing antibiotic decision-making.

Objective: To (1) understand the role of antibiotic-associated adverse events (ABX-AEs) on antibiotic decision-making, (2) understand clinician preferences for ABX-AE feedback, and (3) identify ABX-AEs of greatest clinical concern. Design: Focus groups. Setting: Academic medical center. Participants: Medical and surgical house staff, attending physicians, and advanced practice practitioners. Methods: Focus groups were conducted from May 2022 to December 2022. Participants discussed the role of ABX-AEs in antibiotic decision-making and feedback preferences and evaluated the prespecified categorization of ABX-AEs based on degree of clinical concern. Thematic analysis was conducted using inductive coding. Results: Four focus groups were conducted (n = 15). Six themes were identified. (1) ABX-AE risks during initial prescribing influence the antibiotic prescribed rather than the decision of whether to prescribe. (2) The occurrence of an ABX-AE leads to reassessment of the clinical indication for antibiotic therapy. (3) The impact of an ABX-AE on other management decisions is as important as the direct harm of the ABX-AE. (4) ABX-AEs may be overlooked because of limited feedback regarding the occurrence of ABX-AEs. (5) Clinicians are receptive to feedback regarding ABX-AEs but are concerned about it being punitive. (6) Feedback must be curated to prevent clinicians from being overwhelmed with data. Clinicians generally agreed with the prespecified categorizations of ABX-AEs by degree of clinical concern. Conclusions: The themes identified and assessment of ABX-AEs of greatest clinical concern may inform antibiotic stewardship initiatives that incorporate reporting of ABX-AEs as a strategy to reduce unnecessary antibiotic use.

The metallo-ß-lactamases strike back: emergence of taniborbactam escape variants.

Metallo-ß-lactamases (MBLs) have evolved relatively rapidly to become an international public health threat. There are no clinically available ß-lactamase inhibitors with activity against MBLs. This may change with the introduction of cefepime-taniborbactam. Herein, we review three manuscripts (S. I. Drusin, C. Le Terrier, L. Poirel, R. A. Bonomo, et al., Antimicrob Agents Chemother 68:e01168-23, 2024, https://doi.org/10.1128/aac.01168-23; C. Le Terrier, C. Viguier, P. Nordmann, A. J. Vila, and L. Poirel, Antimicrob Agents Chemother 68:e00991-23, 2024, https://doi.org/10.1128/aac.00991-23; D. Ono, M. F. Mojica, C. R. Bethel, Y. Ishii, et al., Antimicrob Agents Chemother 68:e01332-23, 2024, https://doi.org/10.1128/aac.01332-23) in which investigators describe elegant experiments to explore MBL/taniborbactam interactions and modifications to MBLs, in response, to reduce the affinity of taniborbactam. Challenges with MBL inhibition will not disappear; rather, they will evolve commensurate with advancements in medicinal chemistry.

Transition to Oral Antibiotic Therapy for Hospitalized Adults With Gram-Negative Bloodstream Infections.

Importance: Management of gram-negative bloodstream infections (GN-BSIs) with oral antibiotics is highly variable. Objective: To examine the transition from intravenous (IV) to oral antibiotics, including selection, timing, and associated clinical and microbial characteristics, among hospitalized patients with GN-BSIs. Design, Setting, and Participants: A retrospective cohort study was conducted of 4581 hospitalized adults with GN-BSIs at 24 US hospitals between January 1 and December 31, 2019. Patients were excluded if they died within 72 hours. Patients were excluded from the oral therapy group if transition occurred after day 7. Statistical analysis was conducted from July 2022 to October 2023. Exposures: Administration of antibiotics for GN-BSIs. Main Outcomes and Measures: Baseline characteristics and clinical parameters reflecting severity of illness were evaluated in groups receiving oral and IV therapy. The prevalence of transition from IV to oral antibiotics by day 7, median day of transition, sources of infection, and oral antibiotic selection were assessed. Results: Of a total of 4581 episodes with GN-BSIs (median age, 67 years [IQR, 55-77 years]; 2389 men [52.2%]), 1969 patients (43.0%) receiving IV antibiotics were transitioned to oral antibiotics by day 7. Patients maintained on IV therapy were more likely than those transitioned to oral therapy to be immunosuppressed (833 of 2612 [31.9%] vs 485 of 1969 [24.6%]; P < .001), require intensive care unit admission (1033 of 2612 [39.5%] vs 334 of 1969 [17.0%]; P < .001), have fever or hypotension as of day 5 (423 of 2612 [16.2%] vs 49 of 1969 [2.5%]; P < .001), require kidney replacement therapy (280 of 2612 [10.7%] vs 63 of 1969 [3.2%]; P < .001), and less likely to have source control within 7 days (1852 of 2612 [70.9%] vs 1577 of 1969 [80.1%]; P < .001). Transitioning patients from IV to oral therapy by day 7 was highly variable across hospitals, ranging from 25.8% (66 of 256) to 65.9% (27 of 41). A total of 4109 patients (89.7%) achieved clinical stability within 5 days. For the 3429 episodes (74.9%) with successful source control by day 7, the median day of source control was day 2 (IQR, 1-3 days) for the oral group and day 2 (IQR, 1-4 days) for the IV group (P < .001). Common infection sources among patients administered oral therapy were the urinary tract (1277 of 1969 [64.9%]), hepatobiliary (239 of 1969 [12.1%]), and intra-abdominal (194 of 1969 [9.9%]). The median day of oral transition was 5 (IQR, 4-6 days). Total duration of antibiotic treatment was significantly shorter among the oral group than the IV group (median, 11 days [IQR, 9-14 days] vs median, 13 days [IQR, 8-16 days]; P < .001]. Fluoroquinolones (62.2% [1224 of 1969]), followed by ß-lactams (28.3% [558 of 1969]) and trimethoprim-sulfamethoxazole (11.5% [227 of 1969]), were the most commonly prescribed oral antibiotics. Conclusions and Relevance: In this cohort study of 4581 episodes of GN-BSIs, transition to oral antibiotic therapy by day 7 occurred in fewer than half of episodes, principally with fluoroquinolones, although this practice varied significantly between hospitals. There may have been additional opportunities for earlier and more frequent oral antibiotic transitions because most patients demonstrated clinical stability by day 5.

Identifying Effective Durations of Antibiotic Therapy for the Treatment of Carbapenem-resistant Enterobacterales Bloodstream Infections: A Multicenter Observational Study.

In a propensity-score-weighted cohort of 183 adults with carbapenem-resistant Enterobacterales bacteremia at 24 US hospitals, patients receiving short courses of active therapy (7-10 days, median 9 days) experienced similar odds of recurrent bacteremia or death within 30 days as those receiving prolonged courses of active therapy (14-21 days, median 14 days).

Cefepime versus carbapenems for treatment of AmpC beta-lactamase-producing Enterobacterales bloodstream infections.

PURPOSE: Cefepime is recommended for treating infections caused by AmpC beta-lactamase-producing Enterobacterales (AmpC-PE), though supporting evidence is limited. Therefore, this study compared outcomes associated with cefepime versus carbapenem therapy for bloodstream infections (BSIs) caused by AmpC-PE after phenotypic exclusion of ESBL-co-producing isolates. METHODS: This retrospective cohort study compared definite cefepime versus carbapenem treatment for AmpC-PE BSI in hospitalized patients of the University Hospital Basel, Switzerland, between 01/2015 and 07/2020. Primary outcomes included in-hospital death, renal impairment and neurologic adverse events; secondary outcomes included length of hospital stay and recurrent infection. RESULTS: Two hundred and seventy episodes of AmpC-PE BSI were included, 162, 77 and 31 were treated with a carbapenem, cefepime and other antibiotics, respectively. Patients treated with carbapenems were more likely to be transferred to the ICU on admission and more frequently had central venous catheter as a source of infection. In uni- and multivariable analyses, primary and secondary outcomes did not differ between the two treatment groups, except for more frequent occurrence of neurological adverse events among patients treated with carbapenems and shorter length of hospital stay among survivors treated with cefepime. CONCLUSION: After excluding isolates with phenotypic ESBL-co-production, cefepime was not associated with adverse outcomes compared to carbapenems when used to treat BSIs caused by AmpC-PE. Our study provides evidence to support the use of cefepime as a safe treatment strategy for AmpC-PE BSI, particularly in clinically stable patients without initial renal impairment or increased susceptibility to neurological adverse events.

Is Carbapenem Therapy Necessary for the Treatment of Non-CTX-M ESBL-Producing Enterobacterales Bloodstream Infections?

BACKGROUND: Investigations into antibiotics for extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) bloodstream infections (BSIs) have focused on blaCTX-M genes. Outcomes of patients with non-CTX-M-producing ESBL-E BSIs and optimal treatment are unknown. METHODS: A multicenter observational study investigating 500 consecutive patients with ceftriaxone-resistant Enterobacterales BSIs during 2018-2022 was conducted. Broth microdilution and whole genome sequencing confirmed antibiotic susceptibilities and ESBL gene presence, respectively. Inverse probability weighting (IPW) using propensity scores was employed to ensure patients infected with non-CTX-M and CTX-M ESBL-E BSIs were similar prior to evaluation of outcomes. RESULTS: 396 patients (79.2%) were confirmed to have an ESBL-E BSI. ESBL gene family prevalence was as follows: blaCTX-M (n=370), blaSHV (n=16), blaOXY (n=12), and blaVEB (n=5). ESBL gene identification was not limited to Escherichia coli and Klebsiella species. In the IPW cohort, there was no difference in 30-day mortality or ESBL-E infection recurrence between the non-CTX-M and CTX-M groups (OR=.99, 95% CI 0.87-1.11; p=0.83) and (OR=1.10, 95% CI 0.85--1.42; p=0.47), respectively. In an exploratory analysis limited to the non-CTX-M group, 86% of the 21 patients receiving meropenem were alive on day 30; none of the 5 patients receiving piperacillin-tazobactam were alive on day 30. CONCLUSIONS: Our findings suggest that non-CTX-M and CTX-M ESBL-producing Enterobacterales BSIs are equally concerning and associated with similar clinical outcomes. Meropenem may be associated with improved survival in patients with non-CTX-M ESBL-E BSIs, underscoring the potential benefit of comprehensive molecular diagnostics to enable early antibiotic optimization for patients with ESBL-E BSI, beyond just blaCTX-M genes.

Interlaboratory comparison of Pseudomonas aeruginosa phage susceptibility testing.

Standardized approaches to phage susceptibility testing (PST) are essential to inform selection of phages for study in patients with bacterial infections. There is no reference standard for assessing bacterial susceptibility to phage. We compared agreement between PST performed at three centers: two centers using a liquid assay standardized between the sites with the third, a plaque assay. Four Pseudomonas aeruginosa phages: PaWRA01ø11 (EPa11), PaWRA01ø39 (EPa39), PaWRA02ø83 (EPa83), PaWRA02ø87 (EPa87), and a cocktail of all four phages were tested against 145 P. aeruginosa isolates. Comparisons were made within measurements at the two sites performing the liquid assay and between these two sites. Agreement was assessed based on coverage probability (CP8), total deviation index, concordance correlation coefficient (CCC), measurement accuracy, and precision. For the liquid assay, there was satisfactory agreement among triplicate measurements made on different days at site 1, and high agreement based on accuracy and precision between duplicate measurements made on the same run at site 2. There was fair accuracy between measurements of the two sites performing the liquid assay, with CCCs below 0.6 for all phages tested. When compared to the plaque assay (performed once at site 3), there was less agreement between results of the liquid and plaque assays than between the two sites performing the liquid assay. Similar findings to the larger group were noted in the subset of 46 P. aeruginosa isolates from cystic fibrosis. Results of this study suggest that reproducibility of PST methods needs further development.

Priorities and Progress in Gram-negative Bacterial Infection Research by the Antibacterial Resistance Leadership Group.

Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.

Trimethoprim-Sulfamethoxazole for Pediatric Osteoarticular Infections.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) is active against most Staphylococcus aureus isolates but is not widely used for the treatment of pediatric osteoarticular infections. METHODS: This was a comparative effectiveness study of hospitalized patients ≤18 years treated with TMP-SMX vs. other antibiotic regimens for acute osteoarticular infections between 2016 and 2021 at 3 hospitals using inverse probability of treatment weighted propensity score analysis. The primary outcome was treatment failure, a composite of unanticipated emergency department (ED) or outpatient visits, hospital readmissions, extension, or change of antibiotic therapy due to inadequate clinical response, or death, all within 6 months after completing antibiotics. The secondary outcome was antibiotic-associated adverse events (AEs) within 6 months. The exposed group for the treatment failure analysis included children who received ≥7 days of TMP-SMX and did not experience treatment failure while on another antibiotic. Children receiving at least 1 dose of TMP-SMX were the exposed group for the AE analysis. RESULTS: One-hundred and sixteen patients met eligibility criteria; 26 (22.4%) patients were classified into the TMP-SMX cohort and 90 (77.6%) into the other antibiotics cohort (most commonly clindamycin, vancomycin, and cefazolin). There was no significant difference in treatment failure between TMP-SMX and other antibiotics (43% vs. 19%; 95% CI .9-10.4). More patients in the TMP-SMX cohort experienced an unplanned ED or outpatient visit (OR 4.8, 95% CI 1.3-17.8). There was no difference in hospital readmission, antibiotic change, or duration extension. Exposure to TMP-SMX was associated with more AEs (41% vs. 19%, P = .012). CONCLUSIONS: Treatment with TMP-SMX was not associated with greater clinical failure but was associated with more AEs compared to alternative agents for the treatment of pediatric acute osteoarticular infections.

Refractory Pseudomonas aeruginosa infections treated with phage PASA16: A compassionate use case series.

BACKGROUND: A growing number of compassionate phage therapy cases were reported in the last decade, with a limited number of clinical trials conducted and few unsuccessful clinical trials reported. There is only a little evidence on the role of phages in refractory infections. Our objective here was to present the largest compassionate-use single-organism/phage case series in 16 patients with non-resolving Pseudomonas aeruginosa infections. METHODS: We summarized clinical phage microbiology susceptibility data, administration protocol, clinical data, and outcomes of all cases treated with PASA16 phage. In all intravenous phage administrations, PASA16 phage was manufactured and provided pro bono by Adaptive Phage Therapeutics. PASA16 was administered intravenously, locally to infection site, or by topical use to 16 patients, with data available for 15 patients, mainly with osteoarticular and foreign-device-associated infections. FINDINGS: A few minor side effects were noted, including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 patients (86.6%). Two clinical failures were reported. The minimum therapy duration was 8 days with a once- to twice-daily regimen. CONCLUSIONS: PASA16 with antibiotics was found to be relatively successful in patients for whom traditional treatment approaches have failed previously. Such pre-phase-1 cohorts can outline potential clinical protocols and facilitate the design of future trials. FUNDING: The study was funded in part by The Israeli Science Foundation IPMP (ISF_1349/20), Rosetrees Trust (A2232), United States-Israel Binational Science Foundation (2017123), and the Milgrom Family Support Program.

Epidemiology of Gram-Negative Bloodstream Infections in the United States: Results From a Cohort of 24 Hospitals.

Background: To address knowledge gaps in management of Gram-negative bloodstream infection, the Antibiotic Stewardship Implementation Collaborative was established consisting of programs from 24 academic and community hospitals across the United States. Methods: A retrospective cohort study was conducted of unique adult patients with Gram-negative bloodstream infection hospitalized at participating hospitals from January to December 2019. Patient level and microbiologic data were collected via electronic medical record review with a standardized data collection form and data dictionary. Data analysis was largely descriptive. The Pearson χ2 test to compare categorical variables and the Wilcoxon rank sum test for continuous variables were used. Results: In total, 4851 bacterial isolates from 3710 eligible unique patients were included in the cohort. Most common source of infection was the urinary tract (47.9%). Source control was achieved in 84% of cases. Escherichia coli (2471, 51.0%) was the most common Gram-negative organism recovered. Antibiogram combining isolates from all participating centers with species-level susceptibilities and source specific antibiograms for isolates from urinary, respiratory, and intraabdominal source were created. Northeast sites contributed the most extended spectrum beta-lactamase (ESBL) producing organisms (73%), but West sites had the highest percentage of ESBL producers of total isolates (16%). A statistically significant difference in percentage of ESBL-producing organisms in Whites vs. non-Whites (14.6 % and 9.5 %, respectively, P<0.01) was observed. Conclusions: While the present study was conducted pre-pandemic, it highlights the need for stewardship data collaboratives to enhance our understanding of the antimicrobial resistance patterns.

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/.

An NDM-Producing Escherichia coli Clinical Isolate Exhibiting Resistance to Cefiderocol and the Combination of Ceftazidime-Avibactam and Aztreonam: Another Step Toward Pan-ß-Lactam Resistance.

Background: Cefiderocol and ceftazidime-avibactam plus aztreonam (CZA-ATM) are preferred treatment regimens for New Delhi metallo-ß-lactamase (NDM)-producing infections. Methods: We report the case of a US patient who traveled to India to receive a renal transplant. He subsequently experienced pyelonephritis by an NDM-producing Escherichia coli. Broth microdilution and the broth disk elution method indicated resistance to all ß-lactams, including cefiderocol and CZA-ATM. Whole-genome sequencing investigations were undertaken to identify resistance mechanisms. Results: An E. coli isolate belonging to sequence type (ST) 167 containing a blaNDM-5 gene was identified on a plasmid of the IncFIA/IncFIB/IncFIC replicon groups. When compared with the genome of another ST167 E. coli clinical isolate containing blaNDM-5 and exhibiting susceptibility to cefiderocol and CZA-ATM, a 12-base pair insertion in ftsI, translating to a 4-amino acid duplication in PBP3, was identified. Moreover, a blaCMY-59 gene was harbored on an IncI-γ replicon type, and frameshift mutations were identified in the cirA iron transport gene. Conclusions: This is the first clinical case of a US patient harboring an NDM-producing isolate exhibiting resistance to all available ß-lactam agents. The isolate's unexpected resistance to cefiderocol and CZA-ATM was likely due to a combination of (1) a modified PBP3 (increased MICs to both regimens), (2) truncated iron-binding protein (increased cefiderocol MIC), and (3) a blaCMY gene (reduced CZA-ATM activity). E. coli ST167 clinical isolates harboring blaNDM-5 genes are a recognized international high-risk clone. When coupled with the additional mechanisms identified in our patient's isolate, which is not uncommon for this high-risk clone, pan-ß-lactam resistance may occur.

Infectious Diseases Consultation Associated With Reduced Mortality in Gram-Negative Bacteremia.

Gram-negative bacteremia (GN-BSI) can cause significant morbidity and mortality, but the benefit of infectious diseases consultation (IDC) is not well defined. A 24-site observational cohort study of unique hospitalized patients with 4861 GN-BSI episodes demonstrated a 40% decreased risk of 30-day mortality in patients with IDC compared to those without IDC.

An Electronic Algorithm to Identify Vancomycin-Associated Acute Kidney Injury.

Background: The burden of vancomycin-associated acute kidney injury (V-AKI) is unclear because it is not systematically monitored. The objective of this study was to develop and validate an electronic algorithm to identify cases of V-AKI and to determine its incidence. Methods: Adults and children admitted to 1 of 5 health system hospitals from January 2018 to December 2019 who received at least 1 dose of intravenous (IV) vancomycin were included. A subset of charts was reviewed using a V-AKI assessment framework to classify cases as unlikely, possible, or probable events. Based on review, an electronic algorithm was developed and then validated using another subset of charts. Percentage agreement and kappa coefficients were calculated. Sensitivity and specificity were determined at various cutoffs, using chart review as the reference standard. For courses ≥48 hours, the incidence of possible or probable V-AKI events was assessed. Results: The algorithm was developed using 494 cases and validated using 200 cases. The percentage agreement between the electronic algorithm and chart review was 92.5% and the weighted kappa was 0.95. The electronic algorithm was 89.7% sensitive and 98.2% specific in detecting possible or probable V-AKI events. For the 11 073 courses of ≥48 hours of vancomycin among 8963 patients, the incidence of possible or probable V-AKI events was 14.0%; the V-AKI incidence rate was 22.8 per 1000 days of IV vancomycin therapy. Conclusions: An electronic algorithm demonstrated substantial agreement with chart review and had excellent sensitivity and specificity in detecting possible or probable V-AKI events. The electronic algorithm may be useful for informing future interventions to reduce V-AKI.

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.