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.

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 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.

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.

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.

Highly versatile antibody binding assay for the detection of SARS-CoV-2 infection and vaccination.

Monitoring the burden and spread of infection with the new coronavirus SARS-CoV-2, whether within small communities or in large geographical settings, is of paramount importance for public health purposes. Serology, which detects the host antibody response to the infection, is the most appropriate tool for this task, since virus-derived markers are most reliably detected during the acute phase of infection. Here we show that our ELISA protocol, which is based on antibody binding to the Receptor Binding Domain (RBD) of the S1 subunit of the viral Spike protein expressed as a novel fusion protein, detects antibody responses to SARS-CoV-2 infection and vaccination. We also show that our ELISA is accurate and versatile. It compares favorably with commercial assays widely used in clinical practice to determine exposure to SARS-CoV-2. Moreover, our protocol accommodates use of various blood- and non-blood-derived biospecimens, such as breast milk, as well as dried blood obtained with microsampling cartridges that are appropriate for remote collection. As a result, our RBD-based ELISA protocols are well suited for seroepidemiology and other large-scale studies requiring parsimonious sample collection outside of healthcare settings.

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.

Comparing mortality in patients with carbapenemase-producing carbapenem resistant Enterobacterales and non-carbapenemase-producing carbapenem resistant Enterobacterales bacteremia.

Carbapenem-resistant Enterobacterales (CRE) are classified as either carbapenemase-producing CRE (CP-CRE) or non-carbapenemase-producing CRE (non-CP-CRE) based on their mechanism of carbapenem resistance. Few studies have compared outcomes associated with each type of infection. We attempted to determine if either CRE subset is associated with increased mortality. We performed a retrospective observational study to collect demographic, clinical and outcomes data to compare patients with CP-CRE and non-CP-CRE bacteremia. Of 146 cases analyzed, 88/146 (60%) were CP-CRE and 58/146 (40%) were non-CP-CRE. Patients with CP-CRE bacteremia were less likely to receive active empiric or targeted antibiotic therapy. Non-CP-CRE bacteremia was associated with a 2.4 times higher hazard of death at 30 days after bacteremia onset compared to CP-CRE (HR, 2.4; 95% CI, 1.2, 4.6). Patients with non-CP-CRE bacteremia had a higher hazard of death at 30 days after bacteremia onset compared to those with CP-CRE bacteremia.

Highly versatile antibody binding assay for the detection of SARS-CoV-2 infection.

Monitoring the burden and spread of infection with the new coronavirus SARS-CoV-2, whether within small communities or in large geographical settings, is of paramount importance for public health purposes. Serology, which detects the host antibody response to the infection, is the most appropriate tool for this task, since virus-derived markers are most reliably detected during the acute phase of infection. Here we show that our ELISA protocol, which is based on antibody binding to the Receptor Binding Domain (RBD) of the S1 subunit of the viral Spike protein expressed as a novel fusion protein, detects antibody responses to SARS-CoV-2 infection and COVID-19 vaccination. We also show that our ELISA is accurate and versatile. It compares favorably with commercial assays widely used in clinical practice to determine exposure to SARS-CoV-2. Moreover, our protocol accommodates use of various blood- and non-blood-derived biospecimens, such as breast milk, as well as dried blood obtained with microsampling cartridges that are appropriate for remote collection. As a result, our RBD-based ELISA protocols are well suited for seroepidemiology and other large-scale studies requiring parsimonious sample collection outside of healthcare settings.

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.

Association of Penicillin or Cephalosporin Allergy Documentation and Antibiotic Use in Hospitalized Patients with Pneumonia.

BACKGROUND: Treatment guidelines for pneumonia recommend beta-lactam antibiotic-based therapy. Although reported penicillin allergy is common, more than 90% of patients with reported penicillin allergy are not allergic. OBJECTIVE: We evaluated the association of a documented penicillin and/or cephalosporin (P/C) allergy to antibiotic use for the treatment of inpatient pneumonia. METHODS: This was a national cross-sectional study conducted among Vizient, Inc., network hospitals that voluntarily contributed data. Among hospitalized patients with pneumonia, we examined the relation of a documented P/C allergy in the electronic health record to prevalence of first-line beta-lactam antibiotic administration and alternative antibiotics using multivariable log-binomial regression with generalized estimating equations. RESULTS: Of 2,276 inpatients receiving antibiotics for pneumonia at 95 U.S. hospitals, 450 (20%) had a documented P/C allergy. Compared with pneumonia patients without a documented P/C allergy, patients with a documented P/C allergy had reduced prevalence of first-line beta-lactam antibiotic use (adjusted prevalence ratio [aPR] 0.79; 95% confidence interval [95% CI] 0.69-0.89]). Patients with high-risk P/C reactions (n = 91) had even lower prevalence of first-line beta-lactam antibiotic use (aPR 0.47; 95% CI 0.35-0.64). Alternative antibiotics associated with a higher use in pneumonia patients with a documented P/C allergy included carbapenems (aPR 1.61; 95% CI 1.22-2.13) and fluoroquinolones (aPR 1.52; 95% CI 1.21-1.91). CONCLUSIONS: Inpatients with documented P/C allergy and pneumonia were less likely to receive recommended beta-lactams and more likely to receive carbapenems and fluoroquinolones. Inpatient allergy assessment may improve optimal antibiotic therapy for the 20% of inpatients with pneumonia and a documented P/C allergy.

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.

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.

Microbiology of Meropenem-Vaborbactam: A Novel Carbapenem Beta-Lactamase Inhibitor Combination for Carbapenem-Resistant Enterobacterales Infections.

Vaborbactam is a novel boron-based beta-lactamase inhibitor developed to be effective against Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria. This enzyme is a key driver in the global spread of ß-lactam resistance among carbapenem-resistant Enterobacterales. Alone, vaborbactam has no antibacterial activity; however, the combination of meropenem-vaborbactam has enhanced activity against gram-negative organisms, particularly Enterobacterales with class A and C carbapenemases. Multiple in vitro studies evaluating isolates from various geographic regions, and over different time periods, have demonstrated the high potency of meropenem-vaborbactam against organisms containing KPC2 and KPC3. However, meropenem-vaborbactam does not have activity against OXA-48 or metallo-beta lactamases. This review covers the in vitro studies of meropenem-vaborbactam performed to date, which evaluated both large cohorts of clinical isolates and engineered isolates, to determine efficacy in various settings, including the presence of porin mutations and efflux pump upregulation.

Meropenem-vaborbactam is a new combination antibiotic that was designed specifically for efficacy against bacteria that produce the Klebsiella pneumoniae carbapenemase (KPC) enzyme, which enables resistance to beta-lactam antibiotics. The global spread and increase of difficult-to-treat infections caused by carbapenem-resistant Enterobacterales (CRE) is in part because they produce KPC enzymes. The authors review the in vitro studies of meropenem-vaborbactam activity, which have included isolates from different geographic regions, time periods, and settings, showing that it has high potency against organisms containing KPC enzymes-KPC2 and KPC3. Meropenem-vaborbactam was tested against globally sourced isolates that carried different resistance mechanisms, including carbapenem resistance, multidrug resistant (MDR), and resistance to colistin and/or tigecycline; it inhibited activity of 99.1% Enterobacterales isolates tested at ≤ 1 µg/ml, and at ≤ 8 µg/ml it inhibited 96.5% of MDR isolates and 82% of XDR isolates. Against OXA-48 or metallo-beta lactamase enzymes, meropenem-vaborbactam has limited or no activity, so in the Asia-Pacific region where MLBs are prevalent it was least effective, but and was most effective against US strains where KPC is prevalent. In multiple studies, meropenem-vaborbactam showed strong in vitro activity against E. coli, Enterobacter spp., and K. pneumoniae. Compared to available antibiotics, against both clinical and engineered isolates, as well as engineered E. coli strains with KPC, SHV, and TEM enzymes, meropenem-vaborbactam demonstrated lower MIC values. Overall, in vitro studies of meropenem-vaborbactam have shown enhanced activity against CRE and KPC producers compared to other antibiotics, which is needed in the current CRE environment where KPC is dominant.