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).

Clinical outcomes and emergence of resistance of Pseudomonas aeruginosa infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam.

Few studies compare outcomes of patients with difficult-to-treat resistance (DTR) Pseudomonas aeruginosa infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam. A multicenter prospective study was conducted of unique patients with DTR P. aeruginosa infections from 2018 to 2023 receiving >72 h of ceftolozane-tazobactam or ceftazidime-avibactam, with confirmation that the P. aeruginosa isolate was susceptible to the agent administered by broth microdilution. Inverse probability weighting (IPW) incorporating propensity scores was utilized to ensure balanced baseline characteristics. Regression performed on the post-IPW group determined 30-day mortality and subsequent emergence of resistance (i.e., ≥4-fold increase in MIC) to the initial treatment (i.e., ceftolozane-tazobactam or ceftazidime-avibactam). Among 186 eligible patients, 102 (55%) received ceftolozane-tazobactam and 84 (45%) received ceftazidime-avibactam. In the post-IPW cohort, balance was achieved across all variables [e.g., demographics, severity of illness, severe immunocompromise, Charlson Comorbidity Index ≥5, continuous renal replacement therapy (CRRT), source of infection, combination therapy]. Thirty-day mortality was similar between the ceftolozane-tazobactam and ceftazidime-avibactam groups [21% vs 17%; adjusted odds ratio (aOR): 1.01 (95% confidence interval, CI: 0.90-1.14)]. Emergence of resistance was higher in the ceftolozane-tazobactam group [38% vs 25%; aOR: 1.89 (95% CI: 0.98-4.88)], but did not achieve statistical significance. Prolonged treatment durations and use of CRRT were associated with increased emergence of resistance (both P = 0.04). Although the survival of patients with DTR P. aeruginosa infections appears similar regardless of whether ceftolozane-tazobactam or ceftazidime-avibactam is prescribed, the emergence of resistance may be more concerning with the former. Plausible mechanistic explanations support these findings. Modifiable risk factors were identified that may mitigate this risk.

Defining the Optimal Duration of Therapy for Hospitalized Patients With Complicated Urinary Tract Infections and Associated Bacteremia.

BACKGROUND: Limited data are available to guide effective antibiotic durations for hospitalized patients with complicated urinary tract infections (cUTIs). METHODS: We conducted an observational study of patients ≥18 years at 24 US hospitals to identify the optimal treatment duration for patients with cUTI. To increase the likelihood patients experienced true infection, eligibility was limited to those with associated bacteremia. Propensity scores were generated for an inverse probability of treatment weighted analysis. The primary outcome was recurrent infection with the same species ≤30 days of completing therapy. RESULTS: 1099 patients met eligibility criteria and received 7 (n = 265), 10 (n = 382), or 14 (n = 452) days of therapy. There was no difference in the odds of recurrent infection for patients receiving 10 days and those receiving 14 days of therapy (aOR: .99; 95% CI: .52-1.87). Increased odds of recurrence was observed in patients receiving 7 days versus 14 days of treatment (aOR: 2.54; 95% CI: 1.40-4.60). When limiting the 7-day versus 14-day analysis to the 627 patients who remained on intravenous beta-lactam therapy or were transitioned to highly bioavailable oral agents, differences in outcomes no longer persisted (aOR: .76; 95% CI: .38-1.52). Of 76 patients with recurrent infections, 2 (11%), 2 (10%), and 10 (36%) in the 7-, 10-, and 14-day groups, respectively, had drug-resistant infections (P = .10). CONCLUSIONS: Seven days of antibiotics appears effective for hospitalized patients with cUTI when antibiotics with comparable intravenous and oral bioavailability are administered; 10 days may be needed for all other patients.

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.

Progressive Development of Cefiderocol Resistance in Escherichia coli During Therapy is Associated With an Increase in blaNDM-5 Copy Number and Gene Expression.

BACKGROUND: As cefiderocol is increasingly being prescribed in clinical practice, it is critical that we understand key mechanisms contributing to acquired resistance to this agent. METHODS: We describe a patient with acute lymphoblastic leukemia and a New Delhi metallo-ß-lactamase (NDM)-5-producing Escherichia coli intra-abdominal infection in whom resistance to cefiderocol evolved approximately 2 weeks after the start of treatment. Through whole-genome sequencing (WGS), messenger RNA expression studies, and ethylenediaminetetraacetic acid inhibition analysis, we investigated the role of increased NDM-5 production and genetic mutations contributing to the development of cefiderocol resistance, using 5 sequential clinical E. coli isolates obtained from the patient. RESULTS: In all 5 isolates, blaNDM-5 genes were identified. The minimum inhibitory concentrations for cefiderocol were 2, 4, and >32 µg/mL for isolates 1-2, 3, and 4-5, respectively. WGS showed that isolates 1-3 contained a single copy of the blaNDM-5 gene, whereas isolates 4 and 5 had 5 and 10 copies of the blaNDM-5 gene, respectively, on an IncFIA/FIB/IncFII plasmid. These findings were correlated with those of blaNDM-5 messenger RNA expression analysis, in which isolates 4 and 5 expressed blaNDM-5 1.7- and 2.8-fold, respectively, compared to, isolate 1. Synergy testing with the combination of ceftazidime-avibactam and aztreonam demonstrated expansion of the zone of inhibition between the disks for all isolates. The patient was successfully treated with this combination and remained infection free 1 year later. CONCLUSIONS: The findings in our patient suggest that increased copy numbers of blaNDM genes through translocation events are used by Enterobacterales to evade cefiderocol-mediated cell death. The frequency of increased blaNDM-5 expression in contributing to cefiderocol resistance needs investigation.

Impact of a Prescriber-driven Antibiotic Time-out on Antibiotic Use in Hospitalized Patients.

A multicenter quasi-experimental study of a provider-driven antibiotic "time-out" in 3470 antibiotic courses showed no difference in antibiotic use before and after implementation, but did show a decrease in inappropriate therapy (45% vs 31%, P < .05). Single time-outs without input from antibiotic stewardship teams are insufficient to optimize prescribing.

Failure of clindamycin to eradicate infection with beta-hemolytic streptococci inducibly resistant to clindamycin in an animal model and in human infections.

Inducible clindamycin resistance in beta-hemolytic streptococci remains an underrecognized phenomenon of unknown clinical significance. We performed an evaluation of inducible clindamycin resistance using an animal model as well as retrospectively reviewing the charts of patients treated with clindamycin monotherapy who were infected with beta-hemolytic streptococci inducibly resistant to clindamycin. The neutropenic mouse thigh model of infection was used to evaluate the in vivo activity of clindamycin against beta-hemolytic streptococci, including isolates susceptible, inducibly resistant, or constitutively resistant to clindamycin. The clinical microbiology laboratory information system and pharmacy databases were cross-referenced to identify patients with infections due to inducibly clindamycin-resistant beta-hemolytic streptococci who were treated with clindamycin monotherapy. Medical records of these patients were reviewed to evaluate microbiologic and clinical outcomes. Inducible clindamycin resistance resulted in impaired killing of beta-hemolytic streptococci in the animal model. Though suppressed initially, compared to those with constitutive resistance (P=0.0429), by 48 h, colony counts of inducibly clindamycin-resistant organisms were similar to those of constitutively resistant isolates (P=0.1142). In addition, we identified 8 patients infected with inducibly clindamycin-resistant beta-hemolytic streptococci who experienced clinical and microbiologic failure when treated with clindamycin monotherapy. These patients either improved initially and subsequently failed or never responded to clindamycin therapy. We have demonstrated in a murine model of infection and from human cases that inducible clindamycin resistance in beta-hemolytic streptococci is clinically significant. Routine testing and reporting by clinical laboratories should be encouraged and alternative antimicrobial agents considered when these organisms are encountered in clinical care.

Duration of antibiotics through care transitions: A quality improvement initiative.

Antibiotic resistance is increasing worldwide and can be largely attributed to excess antibiotic use. At our institution, 75% of patients were prescribed excess antibiotic days and total duration of therapy was appropriate in only 24.5% of cases per the reviewers. Choice of antibiotic was appropriate in 70.4% of cases.

The Voice of the Patient: Patient Roles in Antibiotic Management at the Hospital-to-Home Transition.

OBJECTIVE: Our objective was to characterize tasks required for patient-performed antibiotic medication management (MM) at the hospital-to-home transition, as well as barriers to and strategies for patient-led antibiotic MM. Our overall goal was to understand patients' role in managing antibiotics at the hospital-to-home transition. METHODS: We performed a qualitative study including semistructured interviews with health care workers and contextual inquiry with patients discharged home on oral antibiotics. The setting was one academic medical center and one community hospital. Participants included 37 health care workers and 16 patients. We coded interview transcripts and notes from contextual inquiry and developed themes. RESULTS: We identified 6 themes involving barriers or strategies for antibiotic MM. We identified dissonance between participant descriptions of the ease of antibiotic MM at the hospital-to-home transition and their experience of barriers. Similarly, patients did not always recognize when they were experiencing side effects. Lack of access to follow-up care led to unnecessarily long antibiotic courses. Instructions about completing antibiotics were not routinely provided. However, patients typically did not question the need for the prescribed antibiotic. CONCLUSIONS: There are many opportunities to improve patient-led antibiotic MM at the hospital-to-home transition. Mismatches between patient perceptions and patient experiences around antibiotic MM at the hospital-to-home transition provide opportunities for health system improvement.

Hospital-acquired infections among adult patients admitted for coronavirus disease 2019 (COVID-19).

In a multicenter cohort of 963 adults hospitalized due to coronavirus disease 2019 (COVID-19), 5% had a proven hospital-acquired infection (HAI) and 21% had a proven, probable, or possible HAI. Risk factors for proven or probable HAIs included intensive care unit admission, dexamethasone use, severe COVID-19, heart failure, and antibiotic exposure upon admission.

The role of procalcitonin results in antibiotic decision-making in coronavirus disease 2019 (COVID-19).

OBJECTIVE: To evaluate the role of procalcitonin (PCT) results in antibiotic decisions for COVID-19 patients at hospital presentation. DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective observational study of patients ≥18 years hospitalized due to COVID-19 at the Johns Hopkins Health system. Patients who were transferred from another facility with >24 hours stay and patients who died within 48 hours of hospitalization were excluded. METHODS: Elevated PCT values were determined based on each hospital's definition. Antibiotic therapy and PCT results were evaluated for patients with no evidence of bacterial community-acquired pneumonia (bCAP) and patients with confirmed, probable, or possible bCAP. The added value of PCT testing to clinical criteria in detecting bCAP was evaluated using receiving operating curve characteristics (ROC). RESULTS: Of 962 patients, 611 (64%) received a PCT test. ROC curves for clinical criteria and clinical criteria plus PCT test were similar (at 0.5 ng/mL and 0.25 ng/mL). By bCAP group, median initial PCT values were 0.58 ng/mL (interquartile range [IQR], 0.24-1.14), 0.23 ng/mL (IQR, 0.1-0.63), and 0.15 ng/mL (IQR, 0.09-0.35) for proven/probable, possible, and no bCAP groups, respectively. Among patients without bCAP, an elevated PCT level was associated with 1.8 additional days of CAP therapy (95% CI, 1.01-2.75; P < .01) compared to patients with a negative PCT result after adjusting for potential confounders. Duration of CAP therapy was similar between patients without a PCT test ordered and a low PCT level for no bCAP and possible bCAP groups. CONCLUSIONS: PCT results may be abnormal in COVID-19 patients without bCAP and may result in receipt of unnecessary antibiotics.

Failure modes and effects analysis to improve transitions of care in patients discharged on outpatient parenteral antimicrobial therapy.

PURPOSE: To identify barriers to safe and effective completion of outpatient parenteral antimicrobial therapy (OPAT) in patients discharged from an academic medical center and to develop targeted solutions to potentially resolve or improve the identified barriers. SUMMARY: A failure modes and effects analysis (FMEA) was conducted by a multidisciplinary OPAT task force to evaluate the processes for patients discharged on OPAT to 2 postdischarge dispositions: (1) home and (2) skilled nursing facility (SNF). The task force created 2 process maps and identified potential failure modes, or barriers, to the successful completion of each step. Thirteen and 10 barriers were identified in the home and SNF process maps, respectively. Task force members created 5 subgroups, each developing solutions for a group of related barriers. The 5 areas of focus included (1) the OPAT electronic order set, (2) critical tasks to be performed before patient discharge, (3) patient education, (4) patient follow-up and laboratory monitoring, and (5) SNF communication. Interventions involved working with information technology to update the electronic order set, bridging communication and ensuring completion of critical tasks by creating an inpatient electronic discharge checklist, developing patient education resources, planning a central OPAT outpatient database within the electronic medical record, and creating a pharmacist on-call pager for SNFs. CONCLUSION: The FMEA approach was helpful in identifying perceived barriers to successful transitions of care in patients discharged on OPAT and in developing targeted interventions. Healthcare organizations may reproduce this strategy when completing quality improvement planning for this high-risk process.

Development of an antimicrobial stewardship module in an electronic health record: Options to enhance daily antimicrobial stewardship activities.

PURPOSE: The purpose of this manuscript is to describe our experience developing an antimicrobial stewardship (AS) module as a clinical decision support tool in the Epic electronic health record (EHR). SUMMARY: Clinical decision support systems within the EHR can be used to decrease use of broad-spectrum antibiotics, improve antibiotic selection and dosing, decrease adverse effects, reduce antibiotic costs, and reduce the development of antibiotic resistance. The Johns Hopkins Hospital constructed an AS module within Epic. Customized stewardship alerts and scoring systems were developed to triage patients requiring stewardship intervention. This required a multidisciplinary approach with a team comprising AS physicians and pharmacists and Epic information technology personnel, with assistance from clinical microbiology and infection control when necessary. In addition, an intervention database was enhanced with stewardship-specific interventions, and workbench reports were developed specific to AS needs. We herein review the process, advantages, and challenges associated with the development of the Epic AS module. CONCLUSION: Customizing an AS module in an EHR requires significant time and expertise in antimicrobials; however, AS modules have the potential to improve the efficiency of AS personnel in performing daily stewardship activities and reporting through a single system.

A healthcare worker and patient-informed approach to oral antibiotic decision making during the hospital-to-home transition.

In a qualitative study of healthcare workers and patients discharged on oral antibiotics, we identified 5 barriers to antibiotic decision making at hospital discharge: clinician perceptions of patient expectations, diagnostic uncertainty, attending physician-led versus multidisciplinary team culture, not accounting for total antibiotic duration, and need for discharge prior to complete data.

Development of an Electronic Algorithm to Identify in Real Time Adults Hospitalized With Suspected Community-Acquired Pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is a major driver of hospital antibiotic use. Efficient methods to identify patients treated for CAP in real time using the electronic health record (EHR) are needed. Automated identification of these patients could facilitate systematic tracking, intervention, and feedback on CAP-specific metrics such as appropriate antibiotic choice and duration. METHODS: Using retrospective data, we identified suspected CAP cases by searching for patients who received CAP antibiotics AND had an admitting International Classification of Diseases, Tenth Revision (ICD-10) code for pneumonia OR chest imaging within 24 hours OR bacterial urinary antigen testing within 48 hours of admission (denominator query). We subsequently explored different structured and natural language processing (NLP)-derived data from the EHR to identify CAP cases. We evaluated combinations of these electronic variables through receiver operating characteristic (ROC) curves to assess which best identified CAP cases compared to cases identified by manual chart review. Exclusion criteria were age <18 years, absolute neutrophil count <500 cells/mm3, and admission to an oncology unit. RESULTS: Compared to the gold standard of chart review, the area under the ROC curve to detect CAP was 0.63 (95% confidence interval [CI], .55-.72; P < .01) using structured data (ie, laboratory and vital signs) and 0.83 (95% CI, .77-.90; P < .01) when NLP-derived data from radiographic reports were included. The sensitivity and specificity of the latter model were 80% and 81%, respectively. CONCLUSIONS: Creating an electronic tool that effectively identifies CAP cases in real time is possible, but its accuracy is dependent on NLP-derived radiographic data.

Prevalence of Co-infection at the Time of Hospital Admission in COVID-19 Patients, A Multicenter Study.

BACKGROUND: Bacterial infections may complicate viral pneumonias. Recent reports suggest that bacterial co-infection at time of presentation is uncommon in coronavirus disease 2019 (COVID-19); however, estimates were based on microbiology tests alone. We sought to develop and apply consensus definitions, incorporating clinical criteria to better understand the rate of co-infections and antibiotic use in COVID-19. METHODS: A total of 1016 adult patients admitted to 5 hospitals in the Johns Hopkins Health System between March 1, 2020, and May 31, 2020, with COVID-19 were evaluated. Adjudication of co-infection using definitions developed by a multidisciplinary team for this study was performed. Both respiratory and common nonrespiratory co-infections were assessed. The definition of bacterial community-acquired pneumonia (bCAP) included proven (clinical, laboratory, and radiographic criteria plus microbiologic diagnosis), probable (clinical, laboratory, and radiographic criteria without microbiologic diagnosis), and possible (not all clinical, laboratory, and radiographic criteria met) categories. Clinical characteristics and antimicrobial use were assessed in the context of the consensus definitions. RESULTS: Bacterial respiratory co-infections were infrequent (1.2%); 1 patient had proven bCAP, and 11 (1.1%) had probable bCAP. Two patients (0.2%) had viral respiratory co-infections. Although 69% of patients received antibiotics for pneumonia, the majority were stopped within 48 hours in patients with possible or no evidence of bCAP. The most common nonrespiratory infection was urinary tract infection (present in 3% of the cohort). CONCLUSIONS: Using multidisciplinary consensus definitions, proven or probable bCAP was uncommon in adults hospitalized due to COVID-19, as were other nonrespiratory bacterial infections. Empiric antibiotic use was high, highlighting the need to enhance antibiotic stewardship in the treatment of viral pneumonias.

Interaction between enfuvirtide, an injectable fusion inhibitor, and niacin in an HIV-infected patient.

OBJECTIVE: To report a potential drug-drug interaction between enfuvirtide, an injectable HIV fusion inhibitor, and niacin in an HIV-infected man with dilated cardiomyopathy. CASE SUMMARY: A 47-year-old HIV-infected man with dilated cardiomyopathy and prolonged QT syndrome with an automatic implantable cardiovascular defibrillator device was prescribed subcutaneous enfuvirtide 90 mg twice daily as part of his antiretroviral regimen and oral extended-release niacin 500 mg/day for a high-density lipoprotein level of 8 mg/dL. After 1 week of concomitant therapy, the patient began experiencing extreme redness, edema, and swelling at the injection site that corresponded with the flushing sensation due to niacin. This interfered with his daily activities, leading to self-discontinuation of both agents. As the patient had tolerated enfuvirtide therapy prior to the addition of niacin, we reinitiated enfuvirtide with close follow-up, and the patient has been maintained on this agent since then without consequence. Based on the Horn Drug Interaction Probability Scale, a probable interaction occurred between enfurvirtide and niacin. DISCUSSION: We hypothesize that a drug-drug interaction occurs between enfuvirtide and niacin related to prostaglandin synthesis and mobilization of inflammatory cells, specifically Langerhans cells. A theoretical mechanism for this interaction is that the Langerhans cells in the epidermis function improperly due to the presence of HIV and the attachment of enfuvirtide. When these cells are exposed to nicotinic acid, an exaggerated immune response is produced that may lead to pain, redness, and swelling at the injection site. Prostaglandins, cytokines, and other inflammatory molecules may all have a role in this interaction. CONCLUSIONS: Caution should be used when coadministering enfuvirtide and niacin to HIV-infected patients.

Antimicrobial Agents and Catheter Complications in Outpatient Parenteral Antimicrobial Therapy.

OBJECTIVES: Debate about whether certain antimicrobial agents traditionally considered vesicants increase the risk of catheter complications has led to uncertainty in venous catheter placement protocols. To understand whether patients requiring home-based outpatient parenteral antimicrobial therapy (OPAT) should receive peripheral catheters (e.g., midline catheters) versus central venous catheters, and to understand whether certain antimicrobial agents place home-based OPAT patients at higher risk for catheter complications, we investigated associations between antimicrobial agent(s) and catheter complications. METHODS: We performed a prospective cohort study of patients requiring home-based OPAT discharged from two urban tertiary care academic medical centers, including telephone surveys and chart abstractions. Multivariable Poisson regressions were used to evaluate: (i) associations between antimicrobial agents traditionally considered vesicants, based on pH or osmolarity, and catheter complication rates, and (ii) associations between antimicrobial agent and rates of catheter complications. RESULTS: Vesicant antimicrobials defined using pH or osmolarity criteria were not associated with an increased rate of catheter complications (adjusted incidence rate ratio [aIRR]: 1.63, 95% confidence interval [CI]: 0.89-2.96). Vancomycin was associated with an increased rate of catheter complications, as was daptomycin (aIRR: 2.32 [95% CI: 1.20-4.46] and 4.45 [95% CI: 1.02-19.41], respectively). Staphylococcus aureus infections were also associated with an increased rate of catheter complications (aIRR: 2.13, 95% CI: 1.09-4.19), as were midline catheters (aIRR: 9.44, 95% CI: 2.12-41.97). CONCLUSIONS: Our study supports recent guidance identifying vancomycin as a vesicant, among a subset of antimicrobial agents, and removal of pH criteria for identification of vesicants.

Prolonged linezolid use is associated with the development of linezolid-resistant Enterococcus faecium.

We assessed risk factors for and outcomes of linezolid-resistant vancomycin-resistant Enterococcus faecium (LRVREF) bacteremia over 7 years. Thirty-four LRVREF cases were matched to 68 linezolid-susceptible VREF controls. The odds of bacteremia with LRVREF increased by 7% for each additional day of prior linezolid exposure.