Assessing Clinician Utilization of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals : A Retrospective Cohort Study.

BACKGROUND: The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards. OBJECTIVE: To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, plazomicin, eravacycline, imipenem-relebactam-cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics). DESIGN: Retrospective cohort. SETTING: 619 U.S. hospitals. PARTICIPANTS: Adult inpatients. MEASUREMENTS: Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections. RESULTS: Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane-tazobactam (approved 2014) and ceftazidime-avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage. LIMITATION: Residual confounding. CONCLUSION: Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety-efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration; NIH Intramural Research Program.

The microbiological outcomes of culture-negative blood specimens using 16S rRNA broad-range PCR sequencing: a retrospective study in a Canadian province from 2018 to 2022.

Broad-range 16S rRNA PCR and sequencing of 1,183 blood specimens from 853 unique patients yielded an interpretable sequence and bacterial identification in 29%, 16S rRNA amplification with uninterpretable sequences in 53%, and no amplification in 18%. This study highlights the potential utility of this technique in identifying fastidious gram-negative and anaerobic bacteria but the frequent recovery of environmental and contaminant organisms argues for its judicious use. IMPORTANCE: The existing literature focuses on its performance compared to blood cultures in patients with sepsis, leaving a gap in the literature regarding other blood specimens in suspected infectious syndrome across the severity spectrum. We aimed to characterize its microbiological outcomes and provide insight into its potential clinical utility.

Microbiological characterization of Pneumocystis jirovecii pneumonia using quantitative PCR from nasopharyngeal specimens: a retrospective study in a Canadian province from 2019 to 2023.

Bronchoalveolar lavage is usually employed for molecular diagnosis of Pneumocystis jirovecii but requires a specialized procedure. By contrast, nasopharyngeal (NP) specimens are easily obtained. In this retrospective study of 35 patients with paired NP and bronchoscopy specimens, NP specimens had a 100% negative percent agreement (95% CI 80.5-100) but only 72.2% positive percent agreement (95% CI 46.5-90.3).

Reliability of Admission Procalcitonin Testing for Capturing Bacteremia Across the Sepsis Spectrum: Real-World Utilization and Performance Characteristics, 65 U.S. Hospitals, 2008-2017.

OBJECTIVES: Serum procalcitonin is often ordered at admission for patients with suspected sepsis and bloodstream infections (BSIs), although its performance characteristics in this setting remain contested. This study aimed to evaluate use patterns and performance characteristics of procalcitonin-on-admission in patients with suspected BSI, with or without sepsis. DESIGN: Retrospective cohort study. SETTING: Cerner HealthFacts Database (2008-2017). PATIENTS: Adult inpatients (≥ 18 yr) who had blood cultures and procalcitonin drawn within 24 hours of admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Testing frequency of procalcitonin was determined. Sensitivity of procalcitonin-on-admission for detecting BSI due to different pathogens was calculated. Area under the receiver operating characteristic curve (AUC) was calculated to assess discrimination by procalcitonin-on-admission for BSI in patients with and without fever/hypothermia, ICU admission and sepsis defined by Centers for Disease Control and Prevention Adult Sepsis Event criteria. AUCs were compared using Wald test and p values were adjusted for multiple comparisons. At 65 procalcitonin-reporting hospitals, 74,958 of 739,130 patients (10.1%) who had admission blood cultures also had admission procalcitonin testing. Most patients (83%) who had admission day procalcitonin testing did not have a repeat procalcitonin test. Median procalcitonin varied considerably by pathogen, BSI source, and acute illness severity. At a greater than or equal to 0.5 ng/mL cutoff, sensitivity for BSI detection was 68.2% overall, ranging between 58.0% for enterococcal BSI without sepsis and 96.4% for pneumococcal sepsis. Procalcitonin-on-admission displayed moderate discrimination at best for overall BSI (AUC, 0.73; 95% CI, 0.72-0.73) and showed no additional utility in key subgroups. Empiric antibiotic use proportions were not different between blood culture sampled patients with a positive procalcitonin (39.7%) and negative procalcitonin (38.4%) at admission. CONCLUSIONS: At 65 study hospitals, procalcitonin-on-admission demonstrated poor sensitivity in ruling out BSI, moderate-to-poor discrimination for both bacteremic sepsis and occult BSI and did not appear to meaningfully alter empiric antibiotic usage. Diagnostic stewardship of procalcitonin-on-admission and risk assessment of admission procalcitonin-guided clinical decisions is warranted.

Suspected Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) Reinfections: Incidence, Predictors, and Healthcare Use Among Patients at 238 US Healthcare Facilities, 1 June 2020 to 28 February 2021.

In a retrospective cohort study, among 131 773 patients with previous coronavirus disease 2019 (COVID-19), reinfection with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) was suspected in 253 patients (0.2%) at 238 US healthcare facilities between 1 June 2020 and 28 February 2021. Women displayed a higher cumulative reinfection risk. Healthcare burden and illness severity were similar between index and reinfection encounters.

Association Between Caseload Surge and COVID-19 Survival in 558 U.S. Hospitals, March to August 2020.

BACKGROUND: Several U.S. hospitals had surges in COVID-19 caseload, but their effect on COVID-19 survival rates remains unclear, especially independent of temporal changes in survival. OBJECTIVE: To determine the association between hospitals' severity-weighted COVID-19 caseload and COVID-19 mortality risk and identify effect modifiers of this relationship. DESIGN: Retrospective cohort study. (ClinicalTrials.gov: NCT04688372). SETTING: 558 U.S. hospitals in the Premier Healthcare Database. PARTICIPANTS: Adult COVID-19-coded inpatients admitted from March to August 2020 with discharge dispositions by October 2020. MEASUREMENTS: Each hospital-month was stratified by percentile rank on a surge index (a severity-weighted measure of COVID-19 caseload relative to pre-COVID-19 bed capacity). The effect of surge index on risk-adjusted odds ratio (aOR) of in-hospital mortality or discharge to hospice was calculated using hierarchical modeling; interaction by surge attributes was assessed. RESULTS: Of 144 116 inpatients with COVID-19 at 558 U.S. hospitals, 78 144 (54.2%) were admitted to hospitals in the top surge index decile. Overall, 25 344 (17.6%) died; crude COVID-19 mortality decreased over time across all surge index strata. However, compared with nonsurging (<50th surge index percentile) hospital-months, aORs in the 50th to 75th, 75th to 90th, 90th to 95th, 95th to 99th, and greater than 99th percentiles were 1.11 (95% CI, 1.01 to 1.23), 1.24 (CI, 1.12 to 1.38), 1.42 (CI, 1.27 to 1.60), 1.59 (CI, 1.41 to 1.80), and 2.00 (CI, 1.69 to 2.38), respectively. The surge index was associated with mortality across ward, intensive care unit, and intubated patients. The surge-mortality relationship was stronger in June to August than in March to May (slope difference, 0.10 [CI, 0.033 to 0.16]) despite greater corticosteroid use and more judicious intubation during later and higher-surging months. Nearly 1 in 4 COVID-19 deaths (5868 [CI, 3584 to 8171]; 23.2%) was potentially attributable to hospitals strained by surging caseload. LIMITATION: Residual confounding. CONCLUSION: Despite improvements in COVID-19 survival between March and August 2020, surges in hospital COVID-19 caseload remained detrimental to survival and potentially eroded benefits gained from emerging treatments. Bolstering preventive measures and supporting surging hospitals will save many lives. PRIMARY FUNDING SOURCE: Intramural Research Program of the National Institutes of Health Clinical Center, the National Institute of Allergy and Infectious Diseases, and the National Cancer Institute.

Adjunctive Daptomycin in the Treatment of Methicillin-susceptible Staphylococcus aureus Bacteremia: A Randomized, Controlled Trial.

BACKGROUND: Bloodstream infections (BSIs) with methicillin-susceptible Staphylococcus aureus (MSSA) are associated with significant morbidity and mortality. Our objective in this study was to determine the efficacy of synergistic treatment with daptomycin when given with either cefazolin or cloxacillin for the treatment of MSSA BSI. METHODS: A randomized, double-blind, placebo-controlled trial was performed at 2 academic hospitals in Montreal, Canada. Patients aged ≥18 years with MSSA BSI receiving either cefazolin or cloxacillin monotherapy were considered for inclusion. In addition to the standard-of-care treatment, participants received a 5-day course of adjunctive daptomycin or placebo. The primary outcome was the duration of MSSA BSI in days. RESULTS: Of 318 participants screened, 115 were enrolled and 104 were included in the intention-to-treat analysis (median age, 67 years; 34.5% female). The median duration of bacteremia was 2.04 days among patients who received daptomycin vs 1.65 days in those who received placebo (absolute difference, 0.39 days; P = .40). In a modified intention-to-treat analysis that involved participants who remained bacteremic at the time of enrollment, we found a median duration of bacteremia of 3.06 days among patients who received daptomycin vs 3.0 days in those who received placebo (absolute difference, 0.06 days; P = .77). Ninety-day mortality in the daptomycin arm was 18.9% vs 17.7% in the placebo arm (P = 1.0). CONCLUSIONS: Among patients with MSSA BSIs, the administration of adjunctive daptomycin therapy to standard-of-care treatment did not shorten the duration of bacteremia and should not be routinely considered. CLINICAL TRIALS REGISTRATION: NCT02972983.

Assessment of Piperacillin-Tazobactam-Meropenem Synergy against Serine Carbapenemase-Producing Enterobacterales Using Time-Kill Assays.

Synergy between piperacillin-tazobactam and meropenem against KPC-producing Klebsiella pneumoniae was recently demonstrated. We sought to test the combination against a broader range of serine carbapenemase producers. We tested the combination against 10 KPC-producing Escherichia coli and 10 OXA-48 family-producing K. pneumoniae isolates. Antibiotic concentrations used are achievable in critically ill patients. The combination was synergistic against 7 of 10 KPC producers and 9 of 10 OXA-48 producers. There was no synergy detected in control isolates producing NDM-1.

Antibody tests have higher sensitivity at ≥15 days after symptom onset and 99% specificity for detecting SARS-CoV-2.

SOURCE CITATION: Deeks JJ, Dinnes J, Takwoingi Y, et al. Antibody tests for identification of current and past infection with SARS-CoV-2. Cochrane Database Syst Rev. 2020;6:CD013652. 32584464.

Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis: A Diagnostic Study.

Background: Administering antimicrobial agents before obtaining blood cultures could potentially decrease time to treatment and improve outcomes, but it is unclear how this strategy affects diagnostic sensitivity. Objective: To determine the sensitivity of blood cultures obtained shortly after initiation of antimicrobial therapy in patients with severe manifestations of sepsis. Design: Patient-level, single-group, diagnostic study. (ClinicalTrials.gov: NCT01867905). Setting: 7 emergency departments in North America. Participants: Adults with severe manifestations of sepsis, including systolic blood pressure less than 90 mm Hg or a serum lactate level of 4 mmol/L or more. Intervention: Blood cultures were obtained before and within 120 minutes after initiation of antimicrobial treatment. Measurements: Sensitivity of blood cultures obtained after initiation of antimicrobial therapy. Results: Of 3164 participants screened, 325 were included in the study (mean age, 65.6 years; 62.8% men) and had repeated blood cultures drawn after initiation of antimicrobial therapy (median time, 70 minutes [interquartile range, 50 to 110 minutes]). Preantimicrobial blood cultures were positive for 1 or more microbial pathogens in 102 of 325 (31.4%) patients. Postantimicrobial blood cultures were positive for 1 or more microbial pathogens in 63 of 325 (19.4%) patients. The absolute difference in the proportion of positive blood cultures between pre- and postantimicrobial testing was 12.0% (95% CI, 5.4% to 18.6%; P < 0.001). Sensitivity of postantimicrobial culture was 52.9% (CI, 42.8% to 62.9%). When the results of other microbiological cultures were included, microbial pathogens were found in 69 of 102 (67.6% [CI, 57.7% to 76.6%]) patients. Limitation: Only a proportion of screened patients were recruited. Conclusion: Among patients with severe manifestations of sepsis, initiation of empirical antimicrobial therapy significantly reduces the sensitivity of blood cultures drawn shortly after treatment initiation. Primary Funding Source: Vancouver Coastal Health, St. Paul's Hospital Foundation Emergency Department Support Fund, the Fonds de recherche Santé-Québec, and the Maricopa Medical Foundation.

In vitro synergy of ß-lactam combinations against KPC-producing Klebsiella pneumoniae strains.

BACKGROUND: Double carbapenem therapy has been promoted as an alternative treatment for infections due to carbapenemase-producing Enterobacteriaceae where carbapenemase inhibitors are unavailable or when other agents have demonstrated toxicity with equally limited evidence. The capacity of other ß-lactams and ß-lactamase inhibitors to provide synergistic activity with carbapenems is unclear. OBJECTIVES: This study sought to investigate the in vitro synergistic potential of other ß-lactam/ß-lactamase combinations with meropenem against KPC producers. METHODS: Time-kill assays were performed on 24 unique strains of KPC-producing Klebsiella pneumoniae. Combinations evaluated included meropenem or imipenem with one of the following: ertapenem, piperacillin/tazobactam or ceftolozane/tazobactam. Concentrations used for each drug were those considered physiologically attainable in patients with a time above the concentration exceeding 40%-50% of the dose interval. Combinations were considered to be synergistic when they reduced bacterial cfu/mL by ≥2 log10 at 24 h as compared with the single most active agent. RESULTS: The combination of piperacillin/tazobactam with meropenem was found to be synergistic against 70.8% of the isolates, followed by ertapenem with meropenem (58.3%) and ceftolozane/tazobactam with meropenem (41.7%). The piperacillin/tazobactam combination was found to be more bactericidal than the other combinations, with 58.3% of isolates demonstrating a ≥4 log10 cfu/mL reduction at 24 h, as compared with 37.5% for ertapenem and 20.8% for ceftolozane/tazobactam combinations. CONCLUSIONS: The combination of piperacillin/tazobactam with meropenem may be a potential therapy against KPC-producing K. pneumoniae when other therapies are unavailable or prohibitively toxic.

Adjunctive linezolid versus clindamycin for toxin inhibition in ß-lactam-treated patients with invasive group A streptococcal infections in 195 US hospitals from 2016 to 2021: a retrospective cohort study with target trial emulation.

BACKGROUND: Adjunctive clindamycin use is associated with survival in invasive group A streptococcus (GAS) infections but increasing clindamycin resistance in GAS has called into question its durability for this indication. Linezolid also inhibits GAS toxin and virulence factor production, but clinical efficacy data remain sparse. METHODS: We retrospectively emulated a target multicentre, non-blinded, non-inferiority trial to assess the efficacy of adjunctive linezolid compared with clindamycin in adult inpatients with invasive GAS infection treated with a ß-lactam using the PINC AI database between 2016 and 2021. Patients were eligible if they had a monomicrobial GAS culture and received adjunctive therapy within 3 days of culture either concurrently or after ß-lactam initiation and completed at least 3 days of ß-lactam therapy. The primary outcome was adjusted risk ratio (aRR) of in-hospital mortality assessed by overlap-weighting using propensity scores. Secondary outcomes were length of stay among survivors and Clostridium difficile infection. FINDINGS: Of 1095 ß-lactam-treated patients with GAS, 829 (76%) received clindamycin and 266 (24%) received linezolid. In the overlap weighted cohort, the receipt of linezolid was not associated with a statistically significant different aRR of in-hospital mortality compared with clindamycin (linezolid: 9·8% [26/266] vs clindamycin: 7·0% [58/829]; aRR: 0·92 [95% CI 0·42 to 1·43]; p=0·76). The risk difference was -0·005 (95% CI -0·05 to 0·04; p=0·81) and fell within the non-inferiority margin of 0·05. The primary analysis results were consistent across important subgroups and sensitivity analyses. Among survivors, median length of stay (adjusted ratio 0·96 [95% CI 0·16 to 0·08]; p=0·47) and C difficile infection risk (aRR 1·76 [95% CI 0·37 to 1·75]; p=0·29) were not statistically significantly different between the two groups. INTERPRETATION: In this emulated trial of adult patients with invasive GAS infections treated with ß-lactam, linezolid appeared non-inferior to clindamycin suggesting linezolid as an alternative for adjunctive antitoxin therapy. FUNDING: The Intramural Research Program of the US National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Disease.

Trends in Empiric Broad-Spectrum Antibiotic Use for Suspected Community-Onset Sepsis in US Hospitals.

Importance: Little is known about the degree to which suspected sepsis drives broad-spectrum antibiotic use in hospitals, what proportion of antibiotic courses are unnecessarily broad in retrospect, and whether these patterns are changing over time. Objective: To describe trends in empiric broad-spectrum antibiotic use for suspected community-onset sepsis. Design, Setting, and Participants: This cross-sectional study used clinical data from adults admitted to 241 US hospitals in the PINC AI Healthcare Database. Eligible participants were aged 18 years or more and were admitted between 2017 and 2021 with suspected community-onset sepsis, defined by a blood culture draw, lactate measurement, and intravenous antibiotic administration on admission. Exposures: Empiric anti-methicillin-resistant Staphylococcus aureus (MRSA) and/or antipseudomonal ß-lactam agent use. Main Outcomes and Measures: Annual rates of empiric anti-MRSA and/or antipseudomonal ß-lactam agent use and the proportion that were likely unnecessary in retrospect based on the absence of ß-lactam resistant gram-positive or ceftriaxone-resistant gram-negative pathogens from clinical cultures obtained through hospital day 4. Annual trends were calculated using mixed-effects logistic regression models, adjusting for patient and hospital characteristics. Results: Among 6 272 538 hospitalizations (median [IQR] age, 66 [53-78] years; 443 465 male [49.6%]; 106 095 Black [11.9%], 65 763 Hispanic [7.4%], 653 907 White [73.1%]), 894 724 (14.3%) had suspected community-onset sepsis, of whom 582 585 (65.1%) received either empiric anti-MRSA (379 987 [42.5%]) or antipseudomonal ß-lactam therapy (513 811 [57.4%]); 311 213 (34.8%) received both. Patients with suspected community-onset sepsis accounted for 1 573 673 of 3 141 300 (50.1%) of total inpatient anti-MRSA antibiotic days and 2 569 518 of 5 211 745 (49.3%) of total antipseudomonal ß-lactam days. Between 2017 and 2021, the proportion of patients with suspected sepsis administered anti-MRSA or antipseudomonal therapy increased from 63.0% (82 731 of 131 275 patients) to 66.7% (101 003 of 151 435 patients) (adjusted OR [aOR] per year, 1.03; 95% CI, 1.03-1.04). However, resistant organisms were isolated in only 65 434 cases (7.3%) (30 617 gram-positive [3.4%], 38 844 gram-negative [4.3%]) and the proportion of patients who had any resistant organism decreased from 9.6% to 7.3% (aOR per year, 0.87; 95% CI, 0.87-0.88). Most patients with suspected sepsis treated with empiric anti-MRSA and/or antipseudomonal therapy had no resistant organisms (527 356 of 582 585 patients [90.5%]); this proportion increased from 88.0% in 2017 to 91.6% in 2021 (aOR per year, 1.12; 95% CI, 1.11-1.13). Conclusions and Relevance: In this cross-sectional study of adults admitted to 241 US hospitals, empiric broad-spectrum antibiotic use for suspected community-onset sepsis accounted for half of all anti-MRSA or antipseudomonal therapy; the use of these types of antibiotics increased between 2017 and 2021 despite resistant organisms being isolated in less than 10% of patients treated with broad-spectrum agents.

Rapid phenotypic testing for detection of carbapenemase- or extended-spectrum ß-lactamase-producing Enterobacterales directly from blood cultures: a systematic review and meta-analysis.

BACKGROUND: Early identification of extended-spectrum ß-lactamase (ESBL) and carbapenemase-producing Enterobacterales (CP-CRE) is critical for timely therapy. Rapid phenotypic tests identifying these resistance mechanisms from pure bacterial colonies have been developed. OBJECTIVES: To determine the operating characteristics of available rapid phenotypic tests when applied directly to positive blood cultures. METHODS OF DATA SYNTHESIS: Bivariate random effects models were used unless convergence was not achieved where we used separate univariate models for sensitivity and specificity. DATA SOURCES: MEDLINE, CENTRAL, Embase, BIOSIS, and Scopus from inception to 16 March 2021. STUDY ELIGIBILITY CRITERIA: Studies using any rapid phenotypic assay for detection of ESBL or CP-CRE directly from blood cultures positive for Enterobacterales, including those utilizing spiked blood cultures. Case reports/series, posters, abstracts, review articles, those with ≤5 resistant isolates, and studies lacking data or without full text were excluded. PARTICIPANTS: Consecutive patient samples (main analysis) or spiked blood cultures (sensitivity analysis). TESTS: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assays (MALDI-TOF) and commercially available chromogenic or immunogenic assays. REFERENCE STANDARD: Conventional laboratory methods and/or polymerase chain reaction (PCR). ASSESSMENT OF RISK OF BIAS: Quality Assessment of Diagnostic Accuracy Studies Version 2 (QUADAS-2). RESULTS: For detection of the ESBL phenotype the respective pooled sensitivities and specificities for consecutive clinical samples were as follows: 94% (95% CI 93-99%) and 97% (95% CI 95-100%) for MALDI-TOF/mass spectrometry (n = 1); and 98% (95% CI 92-100%) and 100% (95% CI 96-100%) for chromogenic assays (n = 7). For the CP-CRE phenotype the respective pooled sensitivity and specificities for consecutive clinical samples were as follows: 100% (95% CI 99-100%) and 100% (95% CI 100-100%) for MALDI-TOF (n = 2); 96% (95% CI 77-99%) and 100% (95% CI 81-100%) for chromogenic assays (n = 4); and 98% (95% CI 96-100%) and 100% (95% CI 100-100%) for immunogenic testing (n = 2). CONCLUSIONS: Rapid phenotypic assays that can be directly applied to positive blood cultures to detect ESBL and carbapenemase production from Enterobacterales exist and, although clinical studies are limited, they appear to have high sensitivity and specificity. Their potential to facilitate patient care through timely identification of bacterial resistance should be further explored.