Guiding antimicrobial stewardship through thoughtful antimicrobial susceptibility testing and reporting strategies: an updated approach in 2023.

Antimicrobial susceptibility test and report guidelines are an important tool for antimicrobial stewardship programs. Since 1972, Tables 1 within the Clinical and Laboratory Standards Institute (CLSI) M100 document have provided a general framework upon which clinical microbiologists and antimicrobial stewardship teams can build algorithms for susceptibility testing and reporting that meet the specific needs of their institution. Many changes were made to Tables 1 in M100-Ed33 to modernize the content to reflect the landscape of current clinical practice, including the growing armamentarium of antimicrobial agents, the emergence of new mechanisms of antimicrobial resistance, the increasing prevalence of infections caused by multidrug-resistant organisms, and updated consensus recommendations for first-choice and alternative agents for treatment. With these items in mind, the CLSI Table 1 ad hoc working group revised Tables 1 with the ultimate goal of supporting institutions in the creation of individualized test and report strategies that support local antimicrobial stewardship program initiatives. These strategies are built on the concepts of selective and cascade reporting. This minireview introduces the concept of CLSI M100-Ed33 Tables 1, describes the changes to Tables 1 introduced in 2023, and provides clinical vignettes that demonstrate how Tables 1 can be used in various scenarios to devise antimicrobial susceptibility test and report strategies.

Impact of a Rapid Molecular Test for Klebsiella pneumoniae Carbapenemase and Ceftazidime-Avibactam Use on Outcomes After Bacteremia Caused by Carbapenem-Resistant Enterobacterales.

BACKGROUND: Patients with bacteremia due to carbapenem-resistant Enterobacterales (CRE) experience delays until appropriate therapy and high mortality rates. Rapid molecular diagnostics for carbapenemases and new ß-lactam/ß-lactamase inhibitors may improve outcomes. METHODS: We conducted an observational study of patients with CRE bacteremia from 2016 to 2018 at 8 New York and New Jersey medical centers and assessed center-specific clinical microbiology practices. We compared time to receipt of active antimicrobial therapy and mortality between patients whose positive blood cultures underwent rapid molecular testing for the Klebsiella pneumoniae carbapenemase (KPC) gene (blaKPC) and patients whose cultures did not undergo this test. CRE isolates underwent antimicrobial susceptibility testing by broth microdilution and carbapenemase profiling by whole-genome sequencing. We also assessed outcomes when ceftazidime-avibactam and polymyxins were used as targeted therapies. RESULTS: Of 137 patients with CRE bacteremia, 89 (65%) had a KPC-producing organism. Patients whose blood cultures underwent blaKPC PCR testing (n = 51) had shorter time until receipt of active therapy (median: 24 vs 50 hours; P = .009) compared with other patients (n = 86) and decreased 14-day (16% vs 37%; P = .007) and 30-day (24% vs 47%; P = .007) mortality. blaKPC PCR testing was associated with decreased 30-day mortality (adjusted odds ratio: .37; 95% CI: .16-.84) in an adjusted model. The 30-day mortality rate was 10% with ceftazidime-avibactam monotherapy and 31% with polymyxin monotherapy (P = .08). CONCLUSIONS: In a KPC-endemic area, blaKPC PCR testing of positive blood cultures was associated with decreased time until appropriate therapy and decreased mortality for CRE bacteremia, and ceftazidime-avibactam is a reasonable first-line therapy for these infections.

What's New in Antibiograms? Updating CLSI M39 Guidance with Current Trends.

A vast amount of antimicrobial susceptibility test (AST) data is generated from routine testing in diagnostic laboratories for the primary purpose of guiding clinicians in antimicrobial therapy decisions for their patients. However, there is additional value for these data when they are compiled at the local, regional, national, and global levels. Cumulative AST data can be used to prepare antibiograms at the individual health care facility level. These reports can be used to gain insight into appropriate empirical therapy options prior to the availability of AST results on an individual patient's isolate. Different types of cumulative AST data reports can also be compiled at the regional, national, and global levels to estimate susceptibility rates in geographic regions, document trends in evolving microbial populations, and recognize the appearance and spread of emerging antimicrobial resistance threats. The first CLSI M39 Guideline for Analysis and Presentation of Cumulative AST Data was published in 2000. Since that time, there have been changes to AST and reporting recommendations as well as the introduction of advanced informatics technologies to analyze and present data. The 5th edition of M39 has taken into consideration these changes to assist those who analyze, present, and utilize routine antibiograms and other types of cumulative AST data reports as well as those who design information systems for the capturing and analyzing of AST data. Furthermore, antimicrobial stewardship programs (ASPs) have expanded considerably, and uses of the antibiogram by ASPs have been addressed. This minireview will remind users of the basic recommendations for analysis and presentation of antibiograms and provide new suggestions to enhance these reports.

Association of ß-Lactam Allergy Documentation and Prophylactic Antibiotic Use in Surgery: A National Cross-Sectional Study of Hospitalized Patients.

Alternative antibiotics for surgical prophylaxis are associated with increased adverse events and surgical site infection compared to cefazolin. In a sample of perioperative inpatients from 100 hospitals in the United States, cefazolin was 9-fold less likely to be used in patients with a documented ß-lactam allergy whereas clindamycin was 45-fold more likely.

Penicillin Allergy Evaluation Access: A National Survey.

In a study of 121 hospitals from 38 US states, 44% had access to an allergist for inpatient consultations and 39% had access to inpatient penicillin skin testing, indicating that the majority of US hospitals lack sufficient resources to address inpatient penicillin allergies.

Ceftaroline as salvage therapy for complicated MRSA bacteremia: case series and analysis.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) is a major cause of morbidity and mortality in hospitalized patients. Ceftaroline fosamil (CPT) is the only available beta-lactam antibiotic with in vitro and in vivo activities against MRSA. There is currently limited clinical experience with CPT in complicated MRSA BSI. MATERIALS AND METHODS: We report a series of eight patients, including three whose strains had reduced susceptibility to vancomycin. RESULTS: CPT monotherapy was successfully used as salvage therapy for complicated MRSA BSI. The median time to documented clearance was 7 days. CONCLUSION: Ceftaroline monotherapy is effective for clearance of refractory MRSA BSI related to implanted devices, endocarditis, and orthopedic infections.

Impact of Vancomycin MIC on Clinical Outcomes of Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia Treated with Vancomycin at an Institution with Suppressed MIC Reporting.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of bacteremia and is associated with significant morbidity and mortality. Prior studies evaluating the association of vancomycin MICs with clinical outcomes in patients with MRSA bacteremia have been inconsistent. This study evaluated the association between vancomycin MICs and 30-day in-hospital mortality rates for patients with MRSA bacteremia. This was a retrospective cohort study of patients with MRSA bacteremia treated with vancomycin for ≥72 h from January 2013 to August 2016. Vancomycin MICs were determined by broth microdilution via automated susceptibility testing methods. Study groups consisted of patients with MRSA isolates that had vancomycin MICs of <2 µg/ml and those with vancomycin MICs of 2 µg/ml. Covariates included demographics, severity of illness, comorbidities, intensive-care unit (ICU) admission, infectious disease consultation, infectious sources, and hospital onset of bacteremia. The primary outcome was 30-day in-hospital mortality. Secondary outcomes included the duration of bacteremia, persistent bacteremia for ≥7 days, recurrence within 30 days, change to alternative antibiotic therapy, and length of hospital stay. Multivariate logistic regression models were analyzed to control for potential confounding variables. A total of 166 patients were included for analysis: 91 patients with vancomycin MICs of <2 µg/ml and 75 patients with vancomycin MICs of 2 µg/ml. In the multivariate logistic regression model, a vancomycin MIC of 2 µg/ml, compared to a MIC of <2 µg/ml, was not significantly associated with 30-day in-hospital mortality after adjustment for confounders. Additionally, all secondary outcomes were not statistically significantly different between study groups. In patients with MRSA bacteremia treated with vancomycin, the vancomycin MIC was not associated with differences in clinical outcomes.

Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection: The TANGO I Randomized Clinical Trial.

Importance: Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections. Objective: To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis. Design, Setting, and Participants: Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (≥18 years) with complicated UTI, stratified by infection type and geographic region. Interventions: Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment. Main Outcomes and Measures: Primary end point for FDA criteria was overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-to-treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was -15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95% CIs were calculated. Results: Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%] women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-tazobactam (difference, 4.5% [95% CI, 0.7% to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenem-vaborbactam vs 105 of 182 (57.7%) with piperacillin-tazobactam (difference, 9.0% [95% CI, -0.9% to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9% [95% CI, -4.2% to 16.0%]; P < .001 for noninferiority). Adverse events were reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-tazobactam. Conclusions and Relevance: Among patients with complicated UTI, including acute pyelonephritis and growth of a baseline pathogen, meropenem-vaborbactam vs piperacillin-tazobactam resulted in a composite outcome of complete resolution or improvement of symptoms along with microbial eradication that met the noninferiority criterion. Further research is needed to understand the spectrum of patients in whom meropenem-vaborbactam offers a clinical advantage. Trial Registration: clinicaltrials.gov Identifier: NCT02166476.

Recommendations From the 2016 Guidelines for the Management of Adults With Hospital-Acquired or Ventilator-Associated Pneumonia.

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) continue to represent the most common nosocomial-associated infections, resulting in significant attributable mortality, increased length of hospital stay, and financial burden.1 The updated Infectious Diseases Society of America (IDSA) guidelines provide guidance on the diagnosis and management of nonimmunocompromised hosts with HAP and VAP.

Unitary Tract Infection Treatment: When to Use What Agents including Beta-lactam Combination Agents.

In this study, the authors review antibiotic treatment options for both acute uncomplicated and complicated urinary tract infection (UTI). In addition, they also review regimens used in the setting of drug-resistant pathogens including vancomycin resistant Enterococcus, extended spectrum beta-lactamase (ESBL) producing Enterobacterals, carbapenem-resistant Enterobacterals and carbapenem-resistant Pseudomonas, which are encountered with increasing frequency.

Clinical evaluation of a fully electronic microfluidic white blood cell analyzer.

The White Blood Cell (WBC) count is one of the key parameters signaling the health of the immune system. Abnormal WBC counts often signal a systemic insult to the body such as an underlying infection or an adverse side effect to medication. Typically, the blood collected is sent to a central lab for testing, and results come back within hours, which is often inconvenient and may delay time-sensitive diagnosis or treatment. Here, we present the CytoTracker, a fully electronic, microfluidic based instant WBC analyzer with the potential to be used at point-of-care. The CytoTracker is a lightweight, portable, affordable platform capable of quantifying WBCs within minutes using only 50 µl of blood (approximately one drop of blood). In this study, we clinically evaluated the accuracy and performance of CytoTracker in measuring WBC and granulocyte counts. A total of 210 adult patients were recruited in the study. We validated the CytoTracker against a standard benchtop analyzer (Horiba Point of Care Hematology Analyzer, ABX Micros 60). Linear dynamic ranges of 2.5 k/µl- 35 k/µl and 0.6 k/µl- 26 k/µl were achieved for total WBC count and granulocyte count with correlation coefficients of 0.97 and 0.98. In addition, we verified CytoTracker's capability of identifying abnormal blood counts with above 90% sensitivity and specificity. The promising results of this clinical validation study demonstrate the potential for the use of the CytoTracker as a reliable and accurate point-of-care WBC analyzer.

Using higher doses to compensate for tubing residuals in extended-infusion piperacillin-tazobactam.

OBJECTIVE: To mathematically assess drug losses due to infusion line residuals and evaluate methods to compensate for drug loss due to residual volumes in intravenous pump tubing. DATA SOURCES: Literature was accessed through Ovid MEDLINE (1996-February 2013), using combinations of the search terms tubing residuals, residual volume, residual medication, intravenous infusions, intravenous injections, piperacillin, piperacillin-tazobactam, ß-lactams, equipment design, infusion pumps, extended infusion, extended administration, and prolonged infusion. In addition, select reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles that involved extended-infusion piperacillin-tazobactam implementation strategies were included in the review. DATA SYNTHESIS: Infusion pump characteristics and tubing residuals can affect extended-infusion piperacillin-tazobactam dosing strategies. Two studies addressing tubing residuals were identified. Both studies recommended increasing infusion volumes to compensate for tubing residuals. One study also recommended decreasing infusion-line dead space by using alternative infusion pump systems. Study calculations suggest that higher doses of piperacillin-tazobactam may be used to account for medication left in tubing residuals if alternative infusion pump systems cannot be obtained, and increased infusion volumes are not an option. CONCLUSIONS: Extended-infusion piperacillin-tazobactam has been used as a method of maximizing pharmacodynamic target attainment. Use of higher doses of piperacillin-tazobactam may be a reasonable method to compensate for drug loss due to residual volumes in large-bore intravenous pump tubing.

Impact of phenotypic rapid diagnostic assay on duration of empiric antibiotics for gram-negative bacteremia.

Objective: Rapid diagnostic tests (RDTs) are increasingly being implemented as antimicrobial stewardship tools to facilitate antibiotic modification and reduce complications related to their overutilization. We measured the clinical impact of a phenotypic RDT with antimicrobial stewardship (AMS) in the setting of gram-negative bacteremia. Setting and participants: In this single-center retrospective cohort study, we evaluated adult patients with gram-negative bacteremia who received at least 72 hours of an antibiotic. Methods: The primary outcome was the duration of empiric antibiotic therapy for gram-negative bacteremia. Secondary outcomes included time-to-directed therapy, proportion of modifications, hospital length of stay (LOS), and subsequent infection with a multidrug-resistant organism (MDRO) or C. difficile infection (CDI). Results: The duration of empiric antibiotics decreased in the RDT+AMS group (4 days vs 2 days; P < .01). Time to directed therapy decreased from 75.0 to 27.9 hours (P < .01). Conclusions: The clinical outcomes of LOS, MDRO, and CDI were reduced. The phenotypic RDT demonstrated an improvement in stewardship measures and clinical outcomes.

Risk Factors and Clinical Outcomes of Candidemia Associated With Severe COVID-19.

COVID-19 can cause serious illness requiring multimodal treatment and is associated with secondary infections. Studies have suggested an increased risk of fungal infections, including candidemia following severe COVID-19 though understanding of risk factors and clinical outcomes remains unclear. OBJECTIVES: To describe clinical characteristics, outcomes and risk factors of candidemia among patients hospitalized with severe COVID-19. DESIGN SETTING AND PARTICIPANTS: A multicenter, case-control study of patients with severe COVID-19 was conducted to evaluate risk factors and clinical outcomes in patients who developed candidemia between August 2020 and August 2021. MAIN OUTCOMES AND MEASURES: Chart review evaluating institutional and patient demographics, clinical and mycological characteristics, concomitant interventions (antibiotics, immunosuppressive agents, parenteral nutrition, degree of oxygen support, mechanical ventilation, surgery), treatment regimens, and outcomes (length of stay and discharge disposition). RESULTS: A total of 275 patients were enrolled in the study, including 91 patients with severe COVID-19 and subsequent candidemia and 184 with severe COVID-19 without candidemia. Most patients received antibiotics prior to candidemia episode (93%), while approximately one-quarter of patients received biologic for COVID-19. In-hospital mortality was significantly higher in the cases compared with the controls (68% vs 40%; p < 0.01). Candida albicans was the most common (53%), followed by C. glabrata (19%). Use of central lines, biologic, and paralytics were independent risk factors for candidemia. CONCLUSIONS AND RELEVANCE: Candidemia following COVID-19 infection is a concern that requires clinical consideration and patient monitoring. Risk factors for the development of candidemia in the setting of COVID-19 infection are largely consistent with traditional risk factors for candidemia in hospitalized patients.

Clinical Outcomes of Patient Subgroups in the TANGO II Study.

INTRODUCTION: Meropenem-vaborbactam (M-V), a new approved antimicrobial, was developed specifically to be effective treatment for the increasingly prevalent and difficult to treat carbapenem-resistant Enterobacterales (CRE) infections. However, registration phase 3 clinical studies offer limited applicability to daily medical practice as they often focus on indications such as urinary tract infections or skin and soft tissue infections, which generally have patients with fewer comorbid conditions that the typical patients who develops infection with CRE. The more useful studies are pathogen-focused trials which do not exclude the more complicated subjects with conditions such as renal failure, immunocompromised status, or exposure to prior antibiotic therapy. METHODS: The TANGO II study was an open-label investigation of M-V compared with the best available treatment (BAT) in hospitalized adults with a confirmed infection that was known or suspected to be a CRE infection. TANGO II specifically included patients with comorbidities, prior antibiotic therapy, renal failure, and immunocompromised status that are typical in patients with a CRE infection. Interim data analysis indicated that a significant benefit was seen for those patients receiving M-V over BAT. This analysis reports on subsets of TANGO II study patients with multiple comorbidities and high severity of illness, specifically those with prior antibiotic therapy, renal failure, and immunocompromised status. A patient case that highlights particular complexities and challenges of treating patients with CRE infections in the real world is also presented. RESULTS: Subjects with comorbid conditions had better outcomes when given M-V rather than BAT. CONCLUSION: M-V is a welcome addition to the antibiotic armamentarium for the treatment of severe CRE infections in complicated patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02168946.

Antibiotic Selection for Suspected Neisseria gonorrhoeae Infection Among Penicillin-Allergic Patients in the Emergency Department.

Objectives While penicillin allergies are commonly reported, their cross-reactivity with beta-lactam antibiotics is minimal. First-line treatment of gonorrheal infections includes a cephalosporin. In emergency department (ED) environments, physicians must consider these potential allergies when selecting antibiotics for a patient with symptoms concerning for sexually transmitted infection (STI). Methods A retrospective chart review of adult patients with symptoms concerning for STI presenting to an urban ED from January 2014 through June 2019 was performed. Chart discovery used search terms of "STI", "STD", "urethritis", "vaginitis", and "gonorrhea". Information abstracted included patient symptoms, type of care provider, antibiotics prescribed or administered in the ED. Results A total of 603 patients met inclusion criteria, of which 31 reported allergies to penicillin antibiotics, and another three reported allergies to cephalosporins. Patients reporting penicillin allergy were less likely to receive a cephalosporin antibiotic (p=0.0081). Patients reporting a non-anaphylactic allergy to penicillin received a cephalosporin at a rate of 92.3%. Patients reporting a penicillin allergy under the care of only an attending physician were less likely to receive a cephalosporin antibiotic compared with those whose care teams included either a resident physician or physician assistant (p=0.00019). Patients reporting a penicillin allergy were more likely to receive alternative antibiotics beyond cephalosporins or azithromycin (p=0.048); the most frequently given additional antibiotics were metronidazole, doxycycline, and levofloxacin. Conclusions  Patients with penicillin allergies represent a recurring challenge for ED physicians when faced with antibiotic selection for STI symptoms concerning for gonorrheal infection. Those with penicillin allergies are significantly less likely to receive a cephalosporin antibiotic, though these remain the only universally accepted treatment for gonorrheal infections. These findings highlight the significant need for further physician and public education on allergies and antibiotic selection.

Assessing the effect of herbicide diuron on river biofilm: A statistical model.

River biofilm communities are the first ones to be exposed to all toxic discharges received via run off from agricultural fields. Hence, changes in river biofilm community structure and growth pattern are considered as indicator of overall health of lotic ecosystem. Toxicants have effect on biofilm biomass, photosynthetic efficiency and chlorophyll a concentrations. Mathematical models may be applied to estimate the overall vigor of riverine ecosystems considering biofilms as indicators. Herein, previous empirical data of Ricart et al. (2009) on long term effects of environmentally relevant concentrations of diuron on biofilm communities of the River Llobregat, Spain was considered as our model inputs. Our objective is to understand the influence of diuron, chlorophyll a concentrations and photosynthetic efficiency on biovolume using a statistical model. The non-linear relationships between biovolume (dependent variable) and diuron, chlorophyll a concentrations and photosynthetic efficiency (independent variables) were represented by constructing three separate basis functions based on day 8 empirical data. Biovolume, due to nonlinear influence as yielded by the basis functions were used in a multiple linear regression model to estimate the net biovolume. Model validation was done based on day 29 empirical data. The experimentally determined biovolume and our model estimated biovolume showed similar trends. Also, diuron and photosynthetic efficiency had significant (p < 0.05) influence on biovolume. Since, the predominance of diatoms as biofilms within periphytic layers is very common in lotic systems, estimation of changes in diatom biovolume will be significant to assess the effect of herbicides. Diatom biovolume of any day (for example day 22) mentioned in the experimental study may be determined by this model, without the requirement of tedious manual biovolume calculation. Our model will be useful in numerous other studies undertaken on the toxic effect of pollutants on biofilms to quickly and accurately estimate the biofilm biovolume.

Effectiveness of an Electronic Automated Antibiotic Time Out Alert in the Setting of Gram-Negative Bacteremia.

To minimize complications associated with over-utilization of antibiotics, many antimicrobial stewardship programs have incorporated an antibiotic time out (ATO); however, limited data are available to support its effectiveness. This was a single-center retrospective cohort study assessing the impact of the automated electronic ATO in the setting of Gram-negative bacteremia. The primary outcome was the proportion of patients who received a modification of therapy within 24 h of final culture results. Secondary outcomes included modification at any point in therapy, time to modification of therapy, time to de-escalation, and days of therapy of broad-spectrum antibiotics. There was a total of 222 patients who met inclusion criteria, 97 patients pre-ATO and 125 patients post-ATO. The primary outcome of modification of therapy within 24 h of final culture results was not significantly different (24% vs. 30%, p = 0.33). The secondary outcome of modification of therapy at any point in therapy was not significantly different between the two groups (65% vs. 67%, p = 0.73). All other secondary outcomes were not significantly different. The ATO alert was not associated with a higher rate of antibiotic modification within 24 h of culture results in patients with GNB. Further efforts are needed to optimize the ATO strategy and antibiotic prescribing practices.