The Growing Threat of NDM-Producing Escherichia coli With Penicillin-Binding Protein 3 Mutations in the United States-Is There a Potential Role for Durlobactam?

We report identification of 5 patients with infections caused by NDM-5-producing Escherichia coli harboring PBP3 mutations that showed reduced susceptibility to aztreonam-avibactam and cefiderocol. Durlobactam, a novel diazabicyclooctane ß-lactamase inhibitor, demonstrated minimum inhibitory concentrations ranging from 0.5 to 2 µg/mL supporting future investigations into a potential role in clinical management.

A novel 2-step process for the management of inpatient beta-lactam allergy labels.

BACKGROUND: Inpatient beta-lactam allergy labels may increase the unnecessary use of aztreonam and non-beta-lactam antibiotics, which can then lead to more adverse events and increased health care costs, OBJECTIVE: To assess the impact of a novel 2-step process (medication history review followed by risk stratification) on rates of beta-lactam delabeling, aztreonam use, and desensitizations on pediatric, adult, and obstetrics inpatients at a tertiary academic center. METHODS: We prospectively collected data on 700 patients who received inpatient consultation from the Beta-Lactam Allergy Evaluation Service between August 2021 and July 2022. Patients were delabeled either by medication review alone, drug challenge alone if with a low-risk history, or penicillin skin test followed by drug challenge if with a high-risk history. Generalized linear regression modeling was used to compare aztreonam days of therapy in the intervention year with the 2 prior years. Drug desensitizations were assessed by electronic chart review. RESULTS: Most of the patients (n = 656 of 700, 94%) had more than or equal to 1 beta-lactam allergy label removed, clarified, or both; 77.9% of these patients (n = 511 of 656) had 587 beta-lactam allergy labels removed. Nearly one-third (n = 149, 27.6%) had 162 allergy labels removed solely by medication history review. All 114 penicillin skin tests performed had negative results, and 98% (8 of 381) of the patients who underwent any drug challenge passed. Only 5.7% of the delabeled patients were relabeled. There was a 27% reduction in aztreonam use (P = .007). Beta-lactam desensitizations were reduced by 80%. CONCLUSION: A full-time inpatient beta-lactam allergy service using medication history review and risk stratification can safely and effectively remove inpatient beta-lactam allergy labels, reduce aztreonam use, and decrease beta-lactam desensitizations.

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/.

High-level ceftazidime/avibactam resistance in Escherichia coli conferred by the novel plasmid-mediated ß-lactamase CMY-185 variant.

OBJECTIVES: To characterize a blaCMY variant associated with ceftazidime/avibactam resistance from a serially collected Escherichia coli isolate. METHODS: A patient with an intra-abdominal infection due to recurrent E. coli was treated with ceftazidime/avibactam. On Day 48 of ceftazidime/avibactam therapy, E. coli with a ceftazidime/avibactam MIC of >256 mg/L was identified from abdominal drainage. Illumina and Oxford Nanopore Technologies WGS was performed on serial isolates to identify potential resistance mechanisms. Site-directed mutants of CMY ß-lactamase were constructed to identify amino acid residues responsible for ceftazidime/avibactam resistance. RESULTS: WGS revealed that all three isolates were E. coli ST410. The ceftazidime/avibactam-resistant strain uniquely acquired a novel CMY ß-lactamase gene, herein called blaCMY-185, harboured on an IncI-γ/K1 conjugative plasmid. The CMY-185 enzyme possessed four amino acid substitutions relative to CMY-2, including A114E, Q120K, V211S and N346Y, and conferred high-level ceftazidime/avibactam resistance with an MIC of 32 mg/L. Single CMY-2 mutants did not confer reduced ceftazidime/avibactam susceptibility. However, double and triple mutants containing N346Y previously associated with ceftazidime/avibactam resistance in other AmpC enzymes, conferred ceftazidime/avibactam MICs ranging between 4 and 32 mg/L as well as reduced susceptibility to the newly developed cephalosporin, cefiderocol. Molecular modelling suggested that the N346Y substitution confers the reduction of avibactam inhibition due to steric hindrance between the side chain of Y346 and the sulphate group of avibactam. CONCLUSIONS: We identified ceftazidime/avibactam resistance in E. coli associated with a novel CMY variant. Unlike other AmpC enzymes, CMY-185 appears to require an additional substitution on top of N346Y to confer ceftazidime/avibactam resistance.

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/.

Infectious Diseases Society of America Guidance on the Treatment of AmpC ß-Lactamase-Producing Enterobacterales, Carbapenem-Resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia Infections.

The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant infections. A previous guidance document focused 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). Here, guidance is provided for treating AmpC ß-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia infections. A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated questions about the treatment of AmpC-E, CRAB, and S. maltophilia infections. Answers are presented as suggested approaches and corresponding rationales. In contrast to guidance in the previous document, published data on the optimal treatment of AmpC-E, CRAB, and S. maltophilia infections are limited. As such, guidance in this document is provided as "suggested approaches" based on clinical experience, expert opinion, and a review of the available literature. 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. Preferred and alternative treatment suggestions are provided, 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. Suggestions apply for both adult and pediatric populations. 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 17 September 2021 and will be updated annually. The most current version of this document, including date of publication, is available at www.idsociety.org/practice-guideline/amr-guidance-2.0/.

New Perspectives on Antimicrobial Agents: Long-Acting Lipoglycopeptides.

The long-acting lipoglycopeptides (LGPs) dalbavancin and oritavancin are semisynthetic antimicrobials with broad and potent activity against Gram-positive bacterial pathogens. While they are approved by the Food and Drug Administration for acute bacterial skin and soft tissue infections, their pharmacological properties suggest a potential role of these agents for the treatment of deep-seated and severe infections, such as bloodstream and bone and joint infections. The use of these antimicrobials is particularly appealing when prolonged therapy, early discharge, and avoidance of long-term intravascular catheter access are desirable or when multidrug-resistant bacteria are suspected. This review describes the current evidence for the use of oritavancin and dalbavancin in the treatment of invasive infections, as well as the hurdles that are preventing their optimal use. Moreover, this review discusses the current knowledge gaps that need to be filled to understand the potential role of LGPs in highly needed clinical scenarios and the ongoing clinical studies that aim to address these voids in the upcoming years.

Antimicrobial stewardship in solid organ transplant recipients: Current challenges and proposed metrics.

BACKGROUND: Solid organ transplant (SOT) recipients are challenging populations for antimicrobial stewardship interventions due to a variety of reasons, including immunosuppression, consequent risk of opportunistic and donor-derived infections, high rates of infection with multi-drug resistant organisms (MDROs), Clostridioides difficile, and need for prolonged antimicrobial prophylaxis. Despite this, data on stewardship interventions and metrics that address the distinct needs of these patients are limited. METHODS: We performed a narrative review of the current state of antimicrobial stewardship in SOT recipients, existing interventions and metrics in this population, and considerations for implementation of transplant-specific stewardship programs. RESULTS: Antimicrobial stewardship metrics are evolving even in the general patient population. Data on metrics applicable to the SOT population are even more limited. Standard process, outcomes, and balancing metrics may not always apply to the SOT population. A successful stewardship program for SOT recipients requires reviewing existing data, applying general stewardship principles, and understanding the nuances of SOT patients. CONCLUSION: As antimicrobial stewardship interventions are being implemented in SOT recipients; new metrics are needed to assess their impact. In conclusion, SOT patients present a challenging but important opportunity for antimicrobial stewards. ABBREVIATIONS: SOT, antimicrobial stewardship program, MDRO, Clostridioides difficile infection, Centers for Disease Control and Prevention, Infectious Diseases Society of America, prospective audit and feedback, hematopoietic cell transplant, cytomegalovirus, trimethoprim-sulfamethoxazole, surgical site infections, nucleic acid amplification testing, days of therapy, defined daily dose, and length of stay.

Infectious Diseases Society of America 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: Antimicrobial-resistant infections are commonly encountered in US hospitals and result in significant morbidity and mortality. This guidance document provides recommendations for the treatment of 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). METHODS: A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated common questions regarding the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Based on review of the published literature and clinical experience, the panel provide recommendations and associated rationale for each recommendation. Because of significant differences in the molecular epidemiology of resistance and the availability of specific anti-infective agents globally, this document focuses on treatment of antimicrobial-resistant infections in the United States. RESULTS: Approaches to empiric treatment selection, duration of therapy, and other management considerations are briefly discussed. The majority of guidance focuses on preferred and alternative treatment recommendations for antimicrobial-resistant infections, assuming that the causative organism has been identified and antibiotic susceptibility testing results are known. Treatment recommendations apply to both adults and children. CONCLUSIONS: The field of antimicrobial resistance is dynamic and rapidly evolving, and the treatment of antimicrobial-resistant infections will continue to challenge clinicians. This guidance document is current as of 17 September 2020. Updates to this guidance document will occur periodically as new data emerge. Furthermore, the panel will expand recommendations to include other problematic gram-negative pathogens in future versions. The most current version of the guidance including the date of publication can be found at www.idsociety.org/practice-guideline/amr-guidance/.

Infectious Diseases Society of America 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: Antimicrobial-resistant infections are commonly encountered in US hospitals and result in significant morbidity and mortality. This guidance document provides recommendations for the treatment of 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). METHODS: A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated common questions regarding the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Based on review of the published literature and clinical experience, the panel provide recommendations and associated rationale for each recommendation. Because of significant differences in the molecular epidemiology of resistance and the availability of specific anti-infective agents globally, this document focuses on treatment of antimicrobial-resistant infections in the United States. RESULTS: Approaches to empiric treatment selection, duration of therapy, and other management considerations are briefly discussed. The majority of guidance focuses on preferred and alternative treatment recommendations for antimicrobial-resistant infections, assuming that the causative organism has been identified and antibiotic susceptibility testing results are known. Treatment recommendations apply to both adults and children. CONCLUSIONS: The field of antimicrobial resistance is dynamic and rapidly evolving, and the treatment of antimicrobial-resistant infections will continue to challenge clinicians. This guidance document is current as of 17 September 2020. Updates to this guidance document will occur periodically as new data emerge. Furthermore, the panel will expand recommendations to include other problematic gram-negative pathogens in future versions. The most current version of the guidance including the date of publication can be found at www.idsociety.org/practice-guideline/amr-guidance/.

Refractory and Resistant Cytomegalovirus After Hematopoietic Cell Transplant in the Letermovir Primary Prophylaxis Era.

BACKGROUND: Cytomegalovirus (CMV) reactivation is one of the most common infectious complications after allogeneic hematopoietic cell transplant (HCT) and may result in significant morbidity and mortality. Primary prophylaxis with letermovir demonstrated a reduction in clinically significant CMV infections (CS-CMVi) in clinical trials of CMV-seropositive HCT recipients. This study aims at exploring the effect of primary letermovir prophylaxis in this population on the incidence and outcomes of refractory or resistant CMV infections. METHODS: This is a single-center, retrospective cohort study of 537 consecutive CMV-seropositive allogeneic HCT recipients cared for between March 2016 and October 2018. Baseline demographics, HCT characteristics, CMV infections, treatment, and mortality data were collected from the electronic medical record. CMV outcomes were defined according to the recently standardized definitions for clinical trials. Characteristics and outcomes were assessed according to receipt of primary letermovir prophylaxis. RESULTS: Of 537 patients identified, 123 received letermovir for primary prophylaxis during the first 100 days after HCT; 414 did not. In a multivariate analysis, primary prophylaxis with letermovir was associated with reductions in CS-CMVi (hazard ratio [HR] 0.26; 95% confidence interval [CI], 0.16-0.41), CMV end-organ disease (HR 0.23; 95% CI, 0.10-0.52), refractory or resistant CMV infection (HR 0.15; 95% CI, 0.04-0.52), and nonrelapse mortality at week 48 (HR 0.55; 95% CI, 0.32-0.93). There was neither resistant CMV nor CMV-related mortality in the primary letermovir prophylaxis group. CONCLUSIONS: Primary letermovir prophylaxis effectively prevents refractory or resistant CMV infections and decreases nonrelapse mortality at week 48, as well as CS-CMVi and CMV disease after allogeneic HCT.

Clostridioides difficile Infection in Cancer and Immunocompromised Patients: Relevance of a Two-step Diagnostic Algorithm and Infecting Ribotypes on Clinical Outcomes.

BACKGROUND: Patients with cancer are particularly vulnerable to Clostridioides difficile infection (CDI). Guidelines recommend a two-step diagnostic algorithm to differentiate carriers from CDI; however, there are limited data for this approach while including other confounding risk factors for diarrhea such as radiation, cytotoxic chemotherapy, and adoptive cell based therapies. METHODS: We conducted a prospective, non-interventional, single center, cohort study of cancer patients with acute diarrhea and C. difficile, identified in stools by nucleic acid amplification tests (NAAT) and culture. Fecal toxin A/B was detected by enzyme immunoassay (EIA) and isolates were ribotyped using 16s rRNA fluorescent sequencing. Patients were followed for 90 days to compare outcomes according to malignancy type, infecting ribotype, and EIA status. RESULTS: We followed 227 patients with a positive NAAT. Of these, 87% were hospitalized and 83% had an active malignancy. EIA was confirmed positive in 80/227 (35%) of patients. Those with EIA+ were older (60 ± 18 years vs 54 ± 19 years., P = .01), more likely to fail therapy [24/80 (30%) vs 26/147 (18%), P = .04] and experience recurrence [20/80 (25%) vs 21/147(14%), P < .05]. We found a low prevalence (22%) of ribotypes historically associated with poor outcomes (002, 018, 027, 56, F078-126, 244) but their presence were associated with treatment failure [17/50 (34%) vs 33/177 (19%), P = .02]. CONCLUSIONS: When compared to cancer patients with fecal NAAT+/EIA-, patients with NAAT+/EIA+ CDI are less likely to respond to therapy and more likely to experience recurrence, particularly when due to ribotypes associated with poor outcomes.

Alterations of the Oral Microbiome and Cumulative Carbapenem Exposure Are Associated With Stenotrophomonas maltophilia Infection in Patients With Acute Myeloid Leukemia Receiving Chemotherapy.

BACKGROUND: Stenotrophomonas maltophilia is increasingly common in patients with acute myeloid leukemia (AML). Little is known about factors that drive S. maltophilia infection. We evaluated the microbiome and cumulative antibiotic use as predictors of S. maltophilia infection in AML patients receiving remission induction chemotherapy (RIC). METHODS: Subanalysis of a prospective, observational cohort of patients with AML receiving RIC between September 2013 and August 2015 was performed. Fecal and oral microbiome samples collected from initiation of RIC until neutrophil recovery were assessed for the relative abundance of Stenotrophomonas via 16S rRNA gene quantitation. The primary outcome, microbiologically proven S. maltophilia infection, was analyzed using a time-varying Cox proportional hazards model. RESULTS: Of 90 included patients, 8 (9%) developed S. maltophilia infection (pneumonia, n = 6; skin-soft tissue, n = 2); 4/8 (50%) patients were bacteremic; and 7/8 (88%) patients with S. maltophilia infection had detectable levels of Stenotrophomonas vs 22/82 (27%) without infection (P < .01). An oral Stenotrophomonas relative abundance of 36% predicted infection (sensitivity, 96%; specificity, 93%). No association of S. maltophilia infection with fecal relative abundance was found. Cumulative meropenem exposure was associated with increased infection risk (hazard ratio, 1.17; 95% confidence interval, 1.01-1.35; P = .03). CONCLUSIONS: Here, we identify the oral microbiome as a potential source for S. maltophilia infection and highlight cumulative carbapenem use as a risk factor for S. maltophilia in leukemia patients. These data suggest that real-time monitoring of the oral cavity might identify patients at risk for S. maltophilia infection.

IS26-mediated amplification of blaOXA-1 and blaCTX-M-15 with concurrent outer membrane porin disruption associated with de novo carbapenem resistance in a recurrent bacteraemia cohort.

BACKGROUND: Approximately half of clinical carbapenem-resistant Enterobacterales (CRE) isolates lack carbapenem-hydrolysing enzymes and develop carbapenem resistance through alternative mechanisms. OBJECTIVES: To elucidate development of carbapenem resistance mechanisms from clonal, recurrent ESBL-positive Enterobacterales (ESBL-E) bacteraemia isolates in a vulnerable patient population. METHODS: This study investigated a cohort of ESBL-E bacteraemia cases in Houston, TX, USA. Oxford Nanopore Technologies long-read and Illumina short-read sequencing data were used for comparative genomic analysis. Serial passaging experiments were performed on a set of clinical ST131 Escherichia coli isolates to recapitulate in vivo observations. Quantitative PCR (qPCR) and qRT-PCR were used to determine copy number and transcript levels of ß-lactamase genes, respectively. RESULTS: Non-carbapenemase-producing CRE (non-CP-CRE) clinical isolates emerged from an ESBL-E background through a concurrence of primarily IS26-mediated amplifications of blaOXA-1 and blaCTX-M-1 group genes coupled with porin inactivation. The discrete, modular translocatable units (TUs) that carried and amplified ß-lactamase genes mobilized intracellularly from a chromosomal, IS26-bound transposon and inserted within porin genes, thereby increasing ß-lactamase gene copy number and inactivating porins concurrently. The carbapenem resistance phenotype and TU-mediated ß-lactamase gene amplification were recapitulated by passaging a clinical ESBL-E isolate in the presence of ertapenem. Clinical non-CP-CRE isolates had stable carbapenem resistance phenotypes in the absence of ertapenem exposure. CONCLUSIONS: These data demonstrate IS26-mediated mechanisms underlying ß-lactamase gene amplification with concurrent outer membrane porin disruption driving emergence of clinical non-CP-CRE. Furthermore, these amplifications were stable in the absence of antimicrobial pressure. Long-read sequencing can be utilized to identify unique mobile genetic element mechanisms that drive antimicrobial resistance.

Does Switching Norepinephrine to Phenylephrine in Septic Shock Complicated by Atrial Fibrillation With Rapid Ventricular Response Improve Time to Rate Control?

BACKGROUND: Atrial fibrillation (AF) frequently develops during critical illness. In septic shock complicated by rapid AF, the use of phenylephrine may be advantageous secondary to its ß-1 sparing properties. However, evidence supporting this strategy is lacking. OBJECTIVE: The purpose of this study is to determine the clinical effect on rate control of transitioning norepinephrine to phenylephrine in septic shock patients who develop AF with a rapid ventricular response (RVR). METHODS: A single-center retrospective study of septic shock patients admitted to the medical or surgical intensive care unit (ICU) who developed AF with RVR (heart rate >110 beats per minute [bpm]). Patients who were switched to phenylephrine were compared to those who remained on norepinephrine. The primary end point was sustained achievement of rate control. A time-varying Cox proportional hazards model was used to assess the primary end point. RESULTS: A total of 67 patients were included in the study, of which 28 were switched to phenylephrine. Baseline characteristics were similar between groups. The unadjusted hazard ratio for achieving rate control was significant at 1.99 (95% confidence interval [CI]: 1.19-3.34; P < .01) for the phenylephrine group. The adjusted hazard ratio was 1.75 (95% CI: 0.86-3.53; P = .12). There were no statistically significant differences in mortality or ICU length of stay. CONCLUSION: Our study suggests a potential clinical effect on achieving rate control when switching to phenylephrine cannot be excluded. It remains unclear if there is a benefit on mortality or length of stay outcomes in critically ill patients.

Activity of Cefiderocol and Comparators against Isolates from Cancer Patients.

Cefiderocol inhibited 97.5% of 478 Gram-negative isolates from cancer patients at ≤4 mg/liter. It had potent activity against extended-spectrum ß-lactamase-positive Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), and nonfermenting Gram-negative bacilli, including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter species isolates. Amikacin, ceftazidime-avibactam, and meropenem had appreciable activity against non-CRE Enterobacteriaceae No comparators were active against multidrug-resistant P. aeruginosa isolates. Only trimethoprim-sulfamethoxazole had appreciable activity against S. maltophilia isolates. Overall, cefiderocol was associated with the lowest level of resistance.

Extended Versus Short-Course Corticosteroid Taper Regimens in the Management of Chronic Obstructive Pulmonary Disease Exacerbations in Critically Ill Patients.

BACKGROUND: Previous literature has suggested that a short course of corticosteroids is similarly effective as an extended course for managing an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, there are limited data regarding the optimal corticosteroid regimen in critically ill patients and the dosing strategies remain highly variable in this population. METHODS: This retrospective cohort study evaluated patients with AECOPD admitted to the intensive care unit within a 2-year period. Patients were divided into short-course (≤5 days) or extended-course (>5 days) corticosteroid taper groups. The primary end point was treatment failure, defined as the need for intubation, reintubation, or noninvasive mechanical ventilation. Secondary end points included the duration of mechanical ventilation, hospital and intensive care unit length of stay, and adverse events. RESULTS: Of the 151 patients who met the inclusion criteria, 94 received an extended taper and 57 received a short taper. Treatment failure occurred in 3 patients, who were all in the extended taper group (P = .17). In a propensity score-matched cohort, the hospital length of stay was 7 days in the short taper group compared to 11 days in the extended taper group (P < .0001). No differences in adverse events were observed. CONCLUSION: A short-course corticosteroid taper in critically ill patients with AECOPD is associated with reduced hospital length of stay and decreased corticosteroid exposure without increased risk of treatment failure. A prospective randomized trial is warranted.

Oral Versus Aerosolized Ribavirin for the Treatment of Respiratory Syncytial Virus Infections in Hematopoietic Cell Transplant Recipients.

BACKGROUND: The use of oral ribavirin (RBV) for respiratory syncytial virus (RSV) infections is not well studied. With the drastic increase in the cost of aerosolized RBV, we aimed to compare outcomes of hematopoietic cell transplant (HCT) recipients treated with oral or aerosolized RBV for RSV infections. METHODS: We reviewed the records of 124 HCT recipients with RSV infections treated with oral or aerosolized RBV from September 2014 through April 2017. An immunodeficiency scoring index (ISI) was used to classify patients as low, moderate, or high risk for progression to lower respiratory infection (LRI) or death. RESULTS: Seventy patients (56%) received aerosolized RBV and 54 (44%) oral RBV. Both groups had a 27% rate of progression to LRI (P = 1.00). Mortality rates did not significantly differ between groups (30-day: aerosolized 10%, oral 9%, P = 1.00; 90-day: aerosolized 23%, oral 11%, P = .10). Classification and regression tree analysis identified ISI ≥7 as an independent predictor of 30-day mortality. For patients with ISI ≥7, 30-day mortality was significantly increased overall, yet remained similar between the aerosolized and oral therapy groups (33% for both). After propensity score adjustment, Cox proportional hazards models showed similar mortality rates between oral and aerosolized therapy groups (30-day: hazard ratio [HR], 1.12 [95% confidence interval {CI}, .345-3.65, P = .845). CONCLUSIONS: HCT recipients with RSV infections had similar outcomes when treated with aerosolized or oral RBV. Oral ribavirin may be an effective alternative to aerosolized RBV, with potential significant cost savings.

Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint.

BACKGROUND: Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. METHODS: Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a ß-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. RESULTS: Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC >27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P = .006), which remained significant after adjusting for infection source and immunosuppression (P = .026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%-5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%-97.9% when the MIC was 1 mg/L. CONCLUSIONS: For enterococcal bacteremia, a daptomycin fAUC/MIC >27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint.

Levofloxacin versus Cefpodoxime for Antibacterial Prophylaxis in Allogeneic Stem Cell Transplantation.

National guidelines recommend antimicrobial prophylaxis for allogeneic stem cell transplant patients during the pre-engraftment period because of increased infection risk during neutropenia. Fluoroquinolones have demonstrated lower rates of bacteremias and incidence of neutropenic fever, but there is limited evidence in the use of alternative antibacterials such as cefpodoxime. The primary objective of this study is to compare the rates of antibiotic prophylaxis failure between levofloxacin and cefpodoxime in allogeneic stem cell transplant recipients. Secondary objectives include comparing and characterizing number and type of infections, mortality at day 100 post-transplant, and hospitalizations for infectious causes in the first 100 days of transplant. This is a single-center, retrospective chart review of adult patients who received an allogeneic stem cell transplant from matched related and matched unrelated donors and antibacterial prophylaxis with levofloxacin or cefpodoxime from January 1, 2011, to October 1, 2014. A total of 142 patients were evaluated (71 levofloxacin, 71 cefpodoxime). Both levofloxacin and cefpodoxime groups had similar rates of neutropenic fever and antibiotic prophylaxis failure (58% versus 58%, P = NS). There were similar incidences of Clostridioides difficile and Multi-drug resistant (MDR) infections among both levofloxacin and cefpodoxime groups. Rates of infections, hospitalizations, and mortality in the first 100 days were similar among both groups. Cefpodoxime can be used as an alternative to levofloxacin for antibiotic prophylaxis in allogeneic stem cell transplant patients.