A comparison of strategies for identifying patients at risk for carbapenem-resistant or extended ß-lactam-resistant Pseudomonas aeruginosa.

OBJECTIVES: To assess risk factors for carbapenem-resistant Pseudomonas aeruginosa (CR) and extended-ß-lactam-resistant P. aeruginosa (EBR) infection/colonization, and to develop and compare tools for predicting isolation of CR and EBR from clinical cultures. METHODS: This retrospective study analysed hospitalized patients with positive P. aeruginosa cultures between 2015 and 2021. Two case-control analyses were performed to identify risk factors and develop scoring tools for distinguishing patients with CR versus carbapenem-susceptible (CS) P. aeruginosa and EBR versus CS P. aeruginosa. The performance of institutionally derived scores, externally derived scores and the presence/absence of key risk factors to predict CR and EBR were then compared. RESULTS: A total of 2379 patients were included. Of these, 8.3% had a positive culture for CR, 5.0% for EBR and 86.7% for CS P. aeruginosa. There was substantial overlap in risk factors for CR and EBR. Institutional risk scores demonstrated modestly higher area under the ROC curve values than external scores for predicting CR (0.67 versus 0.58) and EBR (0.76 versus 0.70). Assessing the presence/absence of ≥1 of the two strongest predictors (prior carbapenem use or CR isolation within 90 days) was slightly inferior to scoring tools for predicting CR, and comparable for predicting EBR. CONCLUSIONS: Clinicians concerned about CR in P. aeruginosa should consider the likelihood of EBR when making treatment decisions. A simple approach of assessing recent history of CR isolation or carbapenem usage performed similarly to more complex scoring tools and offers a more pragmatic way of identifying patients who require coverage for resistant P. aeruginosa.

A quasi-experimental study of a bundled diagnostic stewardship intervention for ventilator-associated pneumonia.

OBJECTIVES: Diagnostic error in the use of respiratory cultures for ventilator-associated pneumonia (VAP) fuels misdiagnosis and antibiotic overuse within intensive care units. In this prospective quasi-experimental study (NCT05176353), we aimed to evaluate the safety, feasibility, and efficacy of a novel VAP-specific bundled diagnostic stewardship intervention (VAP-DSI) to mitigate VAP over-diagnosis/overtreatment. METHODS: We developed and implemented a VAP-DSI using an interruptive clinical decision support tool and modifications to clinical laboratory workflows. Interventions included gatekeeping access to respiratory culture ordering, preferential use of non-bronchoscopic bronchoalveolar lavage for culture collection, and suppression of culture results for samples with minimal alveolar neutrophilia. Rates of adverse safety outcomes, positive respiratory cultures, and antimicrobial utilization were compared between mechanically ventilated patients (MVPs) in the 1-year post-intervention study cohort (2022-2023) and 5-year pre-intervention MVP controls (2017-2022). RESULTS: VAP-DSI implementation did not associate with increases in adverse safety outcomes but did associate with a 20% rate reduction in positive respiratory cultures per 1000 MVP days (pre-intervention rate 127 [95% CI: 122-131], post-intervention rate 102 [95% CI: 92-112], p < 0.01). Significant reductions in broad-spectrum antibiotic days of therapy per 1000 MVP days were noted after VAP-DSI implementation (pre-intervention rate 1199 [95% CI: 1177-1205], post-intervention rate 1149 [95% CI: 1116-1184], p 0.03). DISCUSSION: Implementation of a VAP-DSI was safe and associated with significant reductions in rates of positive respiratory cultures and broad-spectrum antimicrobial use. This innovative trial of a VAP-DSI represents a novel avenue for intensive care unit antimicrobial stewardship. Multicentre trials of VAP-DSIs are warranted.

An Open-Label, Randomized Trial Comparing Fidaxomicin With Oral Vancomycin for the Treatment of Clostridioides difficile Infection in Hospitalized Patients Receiving Concomitant Antibiotics for Concurrent Infections.

BACKGROUND: Recurrent Clostridioides difficile infection (rCDI) occurs frequently, and concomitant antibiotic (CA) during the initial episode for treatment of non-CDI is a major risk factor. We sought to address the comparative efficacy of fidaxomicin versus vancomycin in the setting of CA during the initial CDI episode. METHODS: We conducted a randomized, controlled, open-label trial at 2 hospitals in Ann Arbor, Michigan. We consecutively consented and enrolled hospitalized patients ≥18 years old with diarrhea, a positive test for C. difficile, and ≥1 qualifying CA. Complicated CDI, CDI treatment for >24 hours prior to enrollment, and planned long-term (>12 weeks) CA use were notable exclusions. Clinical cure was defined as resolution of diarrhea for 2 consecutive days maintained until 2 days after therapy, and rCDI as recurrent diarrhea with positive testing ≤30 days after initial treatment. Patients were randomized to fidaxomicin or vancomycin. RESULTS: Baseline characteristics were similar in the 2 groups of 144 patients. Rates of clinical cure (73% vs 62.9%, P = .195) and rCDI (3.3% vs 4.0%; P > .99) were similar for fidaxomicin and vancomycin in the intention-to-treat and per-protocol cohorts, respectively. Only 4 patients developed rCDI. CONCLUSIONS: In this study of patients with CDI receiving CA, a numerically higher proportion were cured with fidaxomicin versus vancomycin, but this result did not reach statistical significance. Overall recurrence was lower than anticipated in both arms compared with previous studies that did not extend duration of CDI treatment during CA. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov (NCT02692651).

Which trial do we need? Combination antimicrobial therapy for hospital-acquired bacterial pneumonia caused by Pseudomonas aeruginosa.

Meropenem therapy will be open-label, while tobramycin or placebo will be administered in a double-blind fashion. The primary trial endpoint will be a composite hierarchical outcome of 1) 28-day all-cause mortality, 2) ventilator-free days, and 3) modified time to clinical stability, evaluated using a win ratio methodology (see below). Secondary trial outcomes will include frequency of safety events (acute kidney injury), resolution of circulatory shock, recurrent HABP, and emergence of meropenem resistance both during treatment and in cases of recurrent infection. Using simulation studies to inform sample size calculations, we estimate that recruitment of 130 patients per treatment arm would provide at least 80% power to detect a win ratio of 1.50 while preserving a two-sided type 1 error rate of 0.05.

Healthcare providers consistently overestimate the diagnostic probability of ventilator-associated pneumonia.

OBJECTIVE: To assess the accuracy of provider estimates of ventilator-associated pneumonia (VAP) diagnostic probability in various clinical scenarios. DESIGN: We conducted a clinical vignette-based survey of intensive care unit (ICU) physicians to evaluate provider estimates of VAP diagnostic probability before and after isolated cardinal VAP clinical changes and VAP diagnostic test results. Responses were used to calculate imputed diagnostic likelihood ratios (LRs), which were compared to evidence-based LRs. SETTING: Michigan Medicine University Hospital, a tertiary-care center. PARTICIPANTS: This study included 133 ICU clinical faculty and house staff. RESULTS: Provider estimates of VAP diagnostic probability were consistently higher than evidence-based diagnostic probabilities. Similarly, imputed LRs from provider-estimated diagnostic probabilities were consistently higher than evidence-based LRs. These differences were most notable for positive bronchoalveolar lavage culture (provider-estimated LR 5.7 vs evidence-based LR 1.4; P < .01), chest radiograph with air bronchogram (provider-estimated LR 6.0 vs evidence-based LR 3.6; P < .01), and isolated purulent endotracheal secretions (provider-estimated LR 1.6 vs evidence-based LR 0.8; P < .01). Attending physicians and infectious disease physicians were more accurate in their LR estimates than trainees (P = .04) and non-ID physicians (P = .03). CONCLUSIONS: Physicians routinely overestimated the diagnostic probability of VAP as well as the positive LRs of isolated cardinal VAP clinical changes and VAP diagnostic test results. Diagnostic stewardship initiatives, including educational outreach and clinical decision support systems, may be useful adjuncts in minimizing VAP overdiagnosis and ICU antibiotic overuse.

Less Is More? Antibiotic Treatment Duration in Pseudomonas aeruginosa Ventilator-Associated Pneumonia.

Recommended antimicrobial treatment durations for ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa have evolved over the past few decades. In this Viewpoint, we provide a narrative review of landmark trials investigating antimicrobial treatment durations for VAP caused by P. aeruginosa, and appraise iterations of expert consensus guidelines based on these data. We highlight strengths and weaknesses of existing data on this topic and provide recommendations for future avenues of study.

Clinical Impact of Ceftriaxone Resistance in Escherichia coli Bloodstream Infections: A Multicenter Prospective Cohort Study.

Background: Ceftriaxone-resistant (CRO-R) Escherichia coli bloodstream infections (BSIs) are common. Methods: This is a prospective cohort of patients with E coli BSI at 14 United States hospitals between November 2020 and April 2021. For each patient with a CRO-R E coli BSI enrolled, the next consecutive patient with a ceftriaxone-susceptible (CRO-S) E coli BSI was included. Primary outcome was desirability of outcome ranking (DOOR) at day 30, with 50% probability of worse outcomes in the CRO-R group as the null hypothesis. Inverse probability weighting (IPW) was used to reduce confounding. Results: Notable differences between patients infected with CRO-R and CRO-S E coli BSI included the proportion with Pitt bacteremia score ≥4 (23% vs 15%, P = .079) and the median time to active antibiotic therapy (12 hours [interquartile range {IQR}, 1-35 hours] vs 1 hour [IQR, 0-6 hours]; P < .001). Unadjusted DOOR analyses indicated a 58% probability (95% confidence interval [CI], 52%-63%) for a worse clinical outcome in CRO-R versus CRO-S BSI. In the IPW-adjusted cohort, no difference was observed (54% [95% CI, 47%-61%]). Secondary outcomes included unadjusted and adjusted differences in the proportion of 30-day mortality between CRO-R and CRO-S BSIs (-5.3% [95% CI, -10.3% to -.4%] and -1.8 [95% CI, -6.7% to 3.2%], respectively), postculture median length of stay (8 days [IQR, 5-13 days] vs 6 days [IQR, 4-9 days]; P < .001), and incident admission to a long-term care facility (22% vs 12%, P = .045). Conclusions: Patients with CRO-R E coli BSI generally have poorer outcomes compared to patients infected with CRO-S E coli BSI, even after adjusting for important confounders.

Rethinking the "Pan-Culture": Clinical Impact of Respiratory Culturing in Patients With Low Pretest Probability of Ventilator-Associated Pneumonia.

Background: Respiratory cultures are often obtained as part of a "pan-culture" in mechanically ventilated patients in response to new fevers or leukocytosis, despite an absence of clinical or radiographic evidence suggestive of pneumonia. Methods: This was a propensity score-stratified cohort study of hospitalized mechanically ventilated adult patients between 2014 and 2019, with a new abnormal temperature or serum white blood cell count (NATW), but without radiographic evidence of pneumonia, change in ventilator requirements, or documentation of purulent secretions. Two patient groups were compared: those with respiratory cultures performed within 36 hours after NATW and those without respiratory cultures performed. The co-primary outcomes were the proportion of patients receiving >2 days of total antibiotic therapy and >2 days of broad-spectrum antibiotic therapy within 1 week after NATW. Results: Of 534 included patients, 113 (21.2%) had respiratory cultures obtained and 421 (78.8%) did not. Patients with respiratory cultures performed were significantly more likely to receive antibiotics for >2 days within 1 week after NATW than those without respiratory cultures performed (total antibiotic: adjusted odds ratio [OR], 2.57; 95% CI, 1.39-4.75; broad-spectrum antibiotic: adjusted OR, 2.47, 95% CI, 1.46-4.20). Conclusions: Performance of respiratory cultures for fever/leukocytosis in mechanically ventilated patients without increasing ventilator requirements, secretion burden, or radiographic evidence of pneumonia was associated with increased antibiotic use within 1 week after incident abnormal temperature and/or white blood cell count. Diagnostic stewardship interventions targeting performance of unnecessary respiratory cultures in mechanically ventilated patients may reduce antibiotic overuse within intensive care units.

Antimicrobial Stewardship and the Infection Control Practitioner: A Natural Alliance.

Antibiotic overuse and misuse has contributed to rising rates of multidrug-resistant organisms and Clostridioides difficile. Decreasing antibiotic misuse has become a national public health priority. This review outlines the goals of antimicrobial stewardship, essential members of the program, implementation strategies, approaches to measuring the program's impact, and steps needed to build a program. Highlighted is the alliance between antimicrobial stewardship programs and infection prevention programs in their efforts to improve antibiotic use, improve diagnostic stewardship for C difficile and asymptomatic bacteriuria, and decrease health care-associated infections and the spread of multidrug-resistant organisms.

Utility of radiographic keyword abstraction for identification of misdiagnosed pneumonia.

Misdiagnosis of bacterial pneumonia is a leading cause of inappropriate antimicrobial use in hospitalized patients. We report a novel strategy of keyword abstraction from chest radiography transcripts that reliably identified patients with pneumonia misdiagnosis and opportunities for antibiotic discontinuation and/or de-escalation.

The Performance of Sepsis-3 Criteria to Predict Mortality Among Patients With Hematologic Malignancy and Post-transplant who Have Suspected Infection.

BACKGROUND: Sepsis is a leading cause of death, particularly in immunocompromised people. The revised definition of sepsis (Sepsis-3) uses the Sequential Organ Failure Assessment (SOFA) and quick SOFA (qSOFA) to identify patients with sepsis. The aim of this study was to evaluate the performance of SOFA, qSOFA, and systemic inflammatory response syndrome (SIRS) in immunocompromised patients. METHODS: Adult immunocompromised patients admitted to Michigan Medicine between 2012 and 2018 with suspected infection were included based on criteria adopted from the Sepsis-3 study. Each clinical score (SOFA ≥2, qSOFA ≥2, SIRS ≥2) was added to the baseline risk model as an ordinal variable as well as a dichotomous variable, and area under the receiver operating characteristic curve (AUROC) values were calculated. In addition, breakpoints of SOFA between 2 and 10 were assessed to identify the breakpoints with the highest sensitivity and specificity for hospital mortality. The analysis was stratified for intensive care unit (ICU) status. RESULTS: Of 2822 immunocompromised patients with a mean age of 56.8±15.6 years, 213 (7.5%) died during hospitalization. When added to the baseline risk model, SOFA score had the greatest predictive validity for hospital mortality (AUROC,0.802; 95% CI, 0.771-0.832), followed by qSOFA (AUROC,0.783; 95% CI, 0.754-0.812) and SIRS (AUROC,0.741; 95% CI, 0.708-0.774). Among the SOFA breakpoints that were evaluated, SOFA ≥6 had the greatest predictive validity and a moderate positive likelihood ratio (2.75) for hospital mortality. CONCLUSIONS: The predictive validity for hospital mortality of qSOFA was similar among immunocompromised patients as that reported in the Sepsis-3 study. The sensitivity of qSOFA ≥2 for hospital mortality was low. SOFA ≥6 might be an effective tool to identify immunocompromised patients with suspected infection at high risk for clinical deterioration.

Novel case of an adult with toxic shock syndrome following COVID-19 infection.

PURPOSE: To report a case of an adult who developed toxic shock syndrome following COVID-19 infection. OBSERVATIONS: A 28-year-old female tested positive for COVID-19. 19 days later, she developed a fever, rash and a burning sensation in both eyes. Her examination revealed mild ocular inflammation with bilateral eyelid and conjunctival involvement. Skin biopsy favored a diagnosis of toxic shock syndrome. She was initiated on corticosteroid eye drops and her ocular symptoms resolved three days later. CONCLUSION AND IMPORTANCE: Toxic shock syndrome is almost always associated with conjunctival inflammation. To our knowledge, this is the first report of an adult patient with toxic shock syndrome following COVID-19 infection. The association between toxic shock syndrome and COVID-19 is unclear; however, patients should be vigilant for symptoms as toxic shock syndrome can progress rapidly and cause multi-organ failure.

Clinical Implications of Microbiologic Treatment Failure in the Setting of Clinical Cure of Bacterial Pneumonia.

BACKGROUND: Microbiologic cure is a common outcome in pneumonia clinical trials, but its clinical significance is incompletely understood. METHODS: We conducted a retrospective cohort study of adult patients hospitalized with bacterial pneumonia who achieved clinical cure. Rates of recurrent pneumonia and death were compared between patients with persistent growth of the index pathogen at the time of clinical cure (microbiologic failure) and those with pathogen eradication (microbiologic cure). RESULTS: Among 441 patients, 237 experienced microbiologic cure and 204 experienced microbiologic failure. Prevalences of comorbidities, ventilator dependence, and severity of acute illness were similar between groups. Patients with microbiologic failure experienced significantly higher rates of recurrent pneumonia or death following clinical cure than patients with microbiologic cure, controlling for comorbid conditions, severity of acute illness, appropriateness of empiric antibiotics, intensive care unit placement, tracheostomy dependence, and immunocompromised status (90-day multivariable adjusted odds ratio [OR], 1.56; 95% confidence interval [CI], 1.04-2.35). This association was observed among patients with pneumonias caused by Staphylococcus aureus (90-day multivariable adjusted OR, 3.69; 95% CI, 1.73-7.90). A trend was observed among pneumonias caused by nonfermenting gram-negative bacilli, but not Enterobacteriaceae or other pathogens. CONCLUSIONS: Microbiologic treatment failure was independently associated with recurrent pneumonia or death among patients with bacterial pneumonia following clinical cure. Microbiologic cure merits further study as a metric to guide therapeutic interventions for patients with bacterial pneumonia.

Meropenem-vaborbactam for adults with complicated urinary tract and other invasive infections.

INTRODUCTION: Complicated urinary tract infections are increasingly caused by multidrug-resistant organisms. Carbapenem-resistant Enterobacteriaceae (CRE) constitute a rising threat among uropathogens with significant morbidity and mortality. Meropenem-vaborbactam is a novel carbapenem and cyclic boronic acid-based beta-lactamase inhibitor combination with potent activity against subtypes of CRE. Areas covered: This article reviews mechanisms of carbapenem resistance, existing treatment options for CRE, and the current evidence to support the use of meropenem-vaborbactam for the treatment of infections caused by subtypes of CRE including complicated urinary tract infections. Expert commentary: Meropenem-vaborbactam is a superior treatment option for infections secondary to Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. It is associated with higher rates of treatment success and lower rates of toxicity than traditional agents and demonstrates a potentially higher barrier to acquired antimicrobial resistance than ceftazidime-avibactam. At present, meropenem-vaborbactam should be regarded as a preferred treatment option for invasive infections secondary to KPC-producing CRE.

Identification of a dominant negative inhibitor of human zinc finger antiviral protein reveals a functional endogenous pool and critical homotypic interactions.

The zinc finger antiviral protein (ZAP) is a host factor with potent antiviral activity when overexpressed in cells. ZAP blocks replication of the prototype alphavirus Sindbis virus (SINV) at a step at or before translation of the incoming viral genome. The mechanism of ZAP anti-SINV activity and the determinants of its antiviral function, however, have not been defined. Here, we have identified a dominant negative inhibitor of human ZAP. Rat ZAP with a cysteine-to-arginine mutation at position 88 (rZAPC88R), previously reported as a nonfunctional form of ZAP, increases SINV growth in cells. These results led us to discover a previously undetectable pool of endogenous functional ZAP within human cells. Investigation of the mechanism of dominant negative inhibition, combined with a comprehensive mutational analysis of the antiviral factor, revealed that homotypic associations are required for ZAP function in limiting SINV propagation.