Amoxicillin-Clavulanate Breakpoints Against Enterobacterales: Rationale for Revision by the Clinical and Laboratory Standards Institute.

Amoxicillin-clavulanate (AMC) is among the most frequently prescribed antibiotics globally. It has broad antibacterial activity against gram-positive, gram-negative, and anaerobic bacteria and has been used to treat infections caused by a broad range of pathogens. AMC breakpoints against Enterobacterales were initially set in the 1980s. However, since that time, increases in antibiotic resistance, advances in pharmacokinetic/pharmacodynamic analyses, and publication of additional clinical data prompted a reassessment by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing. Based on this contemporary reappraisal, the CLSI retained the Enterobacterales breakpoints but revised comments regarding dosing associated with use of the AMC breakpoints in the 2022 supplement of M100. This viewpoint provides insight into the CLSI breakpoint reevaluation process and summarizes the data and rationale used to support these revisions to the AMC Enterobacterales breakpoint.

Association between Socioeconomic Status and Vaccination Hesitancy, Reluctancy and Confidence among Asian-Americans Living in the State of New Jersey.

BACKGROUD: Socioeconomic status (SES) plays a vital role in determining vaccination uptake and attitudes. Vaccine hesitancy varies among different communities, yet knowledge of vaccine attitudes among Asian-Americans is limited. OBJECTIVE: This study aims to investigate the relationship between SES and vaccine attitudes among Asian-Americans in the State of New Jersey (NJ). METHODS: Asian-Americans aged ≥ 18 years living in NJ were included (N = 157). SES was measured by education level, employment type, employment status, and household income. The primary outcomes were vaccine hesitancy, reluctance, and confidence for COVID-19, influenza, and pneumococcal vaccines. Descriptive and inferential statistics were performed. Multivariable logistic regression was used to identify associations between SES and vaccine hesitancy while controlling for confounders such as age, gender, birthplace, and religion. RESULTS: Among 157 participants, 12.1% reported vaccine hesitancy. There was no statistically significant association between vaccine hesitancy and education level (p = 0.68), employment status (p = 1), employment type (p = 0.48), and household income (p = 0.15). Multivariable logistic regression modeling confirmed that none of the SES predictor variables were associated with vaccine hesitancy. However, as exploratory finding, gender was found to be a significant predictor, with males having lower odds of vaccine hesitancy than females (Adjusted OR = 0.14; p < 0.05). Confidence in influenza and pneumococcal vaccines increased during the pandemic, from 62.34% to 70.13% and from 59.2% to 70.51%, respectively. For the COVID-19 vaccine, 73.1% of participants reported having "a lot of confidence" in taking vaccine. CONCLUSION: Most sampled Asian-Americans in NJ have high confidence in taking COVID-19 vaccines, and there is no significant association between vaccine hesitancy and SES.

Simplified urine-based method to detect rifampin underexposure in adults with tuberculosis: a prospective diagnostic accuracy study.

Variable pharmacokinetics of rifampin in tuberculosis (TB) treatment can lead to poor outcomes. Urine spectrophotometry is simpler and more accessible than recommended serum-based drug monitoring, but its optimal efficacy in predicting serum rifampin underexposure in adults with TB remains uncertain. Adult TB patients in New Jersey and Virginia receiving rifampin-containing regimens were enrolled. Serum and urine samples were collected over 24 h. Rifampin serum concentrations were measured using validated liquid chromatography-tandem mass spectrometry, and total exposure (area under the concentration-time curve) over 24 h (AUC0-24) was determined through noncompartmental analysis. The Sunahara method was used to extract total rifamycins, and rifampin urine excretion was measured by spectrophotometry. An analysis of 58 eligible participants, including 15 (26%) with type 2 diabetes mellitus, demonstrated that urine spectrophotometry accurately identified subtarget rifampin AUC0-24 at 0-4, 0-8, and 0-24 h. The area under the receiver operator characteristic curve (AUC ROC) values were 0.80 (95% CI 0.67-0.90), 0.84 (95% CI 0.72-0.94), and 0.83 (95% CI 0.72-0.93), respectively. These values were comparable to the AUC ROC of 2 h serum concentrations commonly used for therapeutic monitoring (0.82 [95% CI 0.71-0.92], P = 0.6). Diabetes status did not significantly affect the AUC ROCs for urine in predicting subtarget rifampin serum exposure (P = 0.67-0.92). Spectrophotometric measurement of urine rifampin excretion within the first 4 or 8 h after dosing is a simple and cost-effective test that accurately predicts rifampin underexposure. This test provides critical information for optimizing tuberculosis treatment outcomes by facilitating appropriate dose adjustments.

Montelukast in hospitalized patients diagnosed with COVID-19.

OBJECTIVE: Several therapeutic agents have been assessed for the treatment of COVID-19, but few approaches have been proven efficacious. Because leukotriene receptor antagonists, such as montelukast have been shown to reduce both cytokine release and lung inflammation in preclinical models of viral influenza and acute respiratory distress syndrome, we hypothesized that therapy with montelukast could be used to treat COVID-19. The objective of this study was to determine if montelukast treatment would reduce the rate of clinical deterioration as measured by the COVID-19 Ordinal Scale. METHODS: We performed a retrospective analysis of COVID-19 confirmed hospitalized patients treated with or without montelukast. We used "clinical deterioration" as the primary endpoint, a binary outcome defined as any increase in the Ordinal Scale value from Day 1 to Day 3 of the hospital stay, as these data were uniformly available for all admitted patients before hospital discharge. Rates of clinical deterioration between the montelukast and non-montelukast groups were compared using the Fisher's exact test. Univariate logistic regression was also used to assess the association between montelukast use and clinical deterioration. A total of 92 patients were analyzed, 30 who received montelukast at the discretion of the treating physician and 62 patients who did not receive montelukast. RESULTS: Patients receiving montelukast experienced significantly fewer events of clinical deterioration compared with patients not receiving montelukast (10% vs 32%, p = 0.022). Our findings suggest that montelukast associates with a reduction in clinical deterioration for COVID-19 confirmed patients as measured on the COVID-19 Ordinal Scale. CONCLUSIONS: Hospitalized COVID-19 patients treated with montelukast had fewer events of clinical deterioration, indicating that this treatment may have clinical activity. While this retrospective study highlights a potential pathway for COVID-19 treatment, this hypothesis requires further study by prospective studies.

Risk Factors and Outcomes of Hospitalized Patients With Severe Coronavirus Disease 2019 (COVID-19) and Secondary Bloodstream Infections: A Multicenter Case-Control Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has become a global pandemic. Clinical characteristics regarding secondary infections in patients with COVID-19 have been reported, but detailed microbiology, risk factors, and outcomes of secondary bloodstream infections (sBSIs) in patients with severe COVID-19 have not been well described. METHODS: We performed a multicenter case-control study including all hospitalized patients diagnosed with severe COVID-19 and blood cultures drawn from 1 March 2020 to 7 May 2020 at 3 academic medical centers in New Jersey. Data collection included demographics, clinical and microbiologic variables, and patient outcomes. Risk factors and outcomes were compared between cases (sBSI) and controls (no sBSI). RESULTS: A total of 375 hospitalized patients were included. There were 128 sBSIs during the hospitalization. For the first set of positive blood cultures, 117 (91.4%) were bacterial and 7 (5.5%) were fungal. Those with sBSI were more likely to have altered mental status, lower mean percentage oxygen saturation on room air, have septic shock, and be admitted to the intensive care unit compared with controls. In-hospital mortality was higher in those with an sBSI versus controls (53.1% vs 32.8%, P = .0001). CONCLUSIONS: We observed that hospitalized adult patients with severe COVID-19 and sBSI had a more severe initial presentation, prolonged hospital course, and worse clinical outcomes. To maintain antimicrobial stewardship principles, further prospective studies are necessary to better characterize risk factors and prediction modeling to better understand when to suspect and empirically treat for sBSIs in severe COVID-19.

Economic and Health Care Burdens of Hepatitis Delta: A Study of Commercially Insured Adults in the United States.

BACKGROUND AND AIMS: The paucity of data regarding the extent of hepatitis delta virus (HDV) associated health care burden in the United States is an important obstacle to assessing the cost-effectiveness of potential intervention strategies. In this study, we characterized the health care use and cost burdens of HDV in the United States using real-world claims data. APPROACH AND RESULTS: We conducted a case-control study using the Truven Health MarketScan Commercial Claims databases from 2011-2014. A total of 2,727 HDV cases were matched 1:1 by sociodemographic characteristics and comorbidities to chronic hepatitis B virus (HBV) controls using propensity scores. The HDV group had significantly higher prevalence of substance abuse, sexually transmitted diseases, decompensated cirrhosis, cirrhosis, and hepatitis C virus compared to patients with chronic HBV. First HDV diagnosis was associated with significant increases in the total number of health care claims (25.61 vs. 28.99; P < 0.0001) and total annual health care costs ($19,476 vs. $23,605; P < 0.0001) compared with pre-HDV baseline. The case-control analysis similarly indicated higher total claims (28.99 vs. 25.19; P < 0.0001) and health care costs ($23,605 vs. $18,228; P < 0.0001) in HDV compared with HBV alone. Compared with HBV controls, HDV cases had an adjusted incident rate ratio of 1.16 (95% confidence interval: 1.10, 1.22) times the total number of annual claims and an adjusted incident rate ratio 1.32 (95% confidence interval 1.17, 1.48) times the total annual health care cost. CONCLUSIONS: HDV is associated with higher health care use and cost burden than HBV alone, underscoring the need for improved screening and treatment.

Prevention of infection and optimizing vaccination in the solid organ transplant candidate and recipient.

PURPOSE OF REVIEW: Infections can result in serious complications in solid organ transplant (SOT) patients. The need to remain up to date on recommendations on screening, vaccinations, and chemoprophylaxis is paramount in the management of SOT patients. The goal of this review is to provide an overview of current recommendations for the prevention of infections and optimization of vaccinations from the pretransplant through posttransplant periods. RECENT FINDINGS: There is an emphasis on thorough pretransplant evaluation to guide clinicians and pretransplant testing based on epidemiological and endemic risk factors. Additionally, recent studies on vaccine safety and efficacy of newer vaccine formulations in SOT recipients are addressed. SUMMARY: This review provides insight on updated recommendations for pretransplant screening, new data on vaccine optimization in SOT recipients and posttransplant prophylaxis. Further research is needed in order to improve preventive measures including screening tests, vaccines, and chemoprophylaxis.

Latent Tuberculosis Infection Beliefs and Testing and Treatment Health Behaviors Amongst Non-US-Born South Asians in New Jersey: A Cross-Sectional Community Survey.

Latent tuberculosis infection (LTBI) remains a problem in the United States as reactivation leads to active TB disease particularly in persons with risk factors. The objective of this study is to assess the knowledge, attitudes and health behaviors related to testing and treatment of LTBI among non-US-born South Asians (SA) in New Jersey (NJ). A cross-sectional, community-based survey was the primary tool for gathering data. Eligibility criteria included being at least 18 years of age, self-identifying as SA, verbal consent for participation, and birth in a high TB endemic country. A hardcopy survey was distributed at local South Asian health fairs. The survey included questions about demographics, knowledge, beliefs on TB, and health behaviors (testing and treatment). Descriptive statistics were performed for all survey responses. Logistic regression models were constructed to assess the association of characteristics/beliefs and study outcomes. The survey sample size included 387 respondents. A total of 197 (54%) of respondents reported ever been tested for TB. Those who were tested for TB were generally younger, had higher educational levels, higher household incomes, and were more likely to have health insurance than those not ever tested for TB. Significantly more respondents who self-reported ever been tested for TB believed that TB was very or extremely serious (71.1% vs. 56.2%, p = 0.004). Also, significantly more respondents who self-reported ever been tested for TB believed that it was important to get tested (91.2% vs. 63.3%, p < 0.001). The survey analysis concluded that high-risk SA residents in NJ demonstrated a low rate of testing for TB.

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 an electronic medical record alert for severe sepsis among ED patients.

BACKGROUND: Severe sepsis and septic shock are a major health concern worldwide. The objective of this study is to determine if Severe Sepsis Best Practice Alert (SS-BPA) implementation was associated with improved processes of care and clinical outcomes among patients with severe sepsis or septic shock presenting to the emergency department (ED). METHODS: This is a single-center, before-and-after observational study. The intervention group (n = 103) consisted of adult patients presenting to the ED with severe sepsis or septic shock during a 7-month period after implementation of the SS-BPA. The control group (n = 111) consisted of patients meeting the same criteria over a prior 7-month period. The SS-BPA primarily acts by automated, real-time, algorithm-based detection of severe sepsis or septic shock via the electronic medical record system. The primary outcome was in-hospital mortality. Secondary outcomes included hospital length of stay (LOS), time to antibiotic administration, and proportion of patients who received antibiotics within the target 60 minutes. RESULTS: Time to antibiotics was significantly reduced in the SS-BPA cohort (29 vs 61.5 minutes, P < .001). In addition, there was a higher proportion of patients who received antibiotics within 60 minutes (76.7 vs 48.6%; P < .001). On multivariable analysis, in-hospital mortality was not significantly reduced in the intervention group (odds ratio, 0.64; 95% confidence interval, 0.26-1.57). Multivariable analysis of LOS indicated a significant reduction among patients in the SS-BPA cohort (geometric mean ratio, 0.66; 95% confidence interval, 0.53-0.82). CONCLUSION: Implementation of the SS-BPA for severe sepsis or septic shock among ED patients is associated with significantly improved timeliness of antibiotic administration and reduced hospital LOS.

Sulbactam-durlobactam: a ß-lactam/ß-lactamase inhibitor combination targeting Acinetobacter baumannii.

Sulbactam-durlobactam is a pathogen-targeted ß-lactam/ß-lactamase inhibitor combination that has been approved by the US FDA for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex (ABC) in patients 18 years of age and older. Sulbactam is a penicillin derivative with antibacterial activity against Acinetobacter but is prone to hydrolysis by ß-lactamases encoded by contemporary isolates. Durlobactam is a diazabicyclooctane ß-lactamase inhibitor with activity against Ambler classes A, C and D serine ß-lactamases that restores sulbactam activity both in vitro and in vivo against multidrug-resistant ABC. Sulbactam-durlobactam is a promising alternative therapy for the treatment of serious Acinetobacter infections, which can have high rates of mortality.

Sulbactam­durlobactam: a drug for treating lung infectionsAcinetobacter is a type of bacteria. One type, called CRAB, causes serious infections and can be fatal. CRAB is very hard to treat because most drugs no longer work. Sulbactam­durlobactam (SUL-DUR) is a drug that can kill CRAB. The US FDA approved SUL-DUR in May of 2023 for treating lung infections (pneumonia) caused by CRAB. This article explains how SUL-DUR works. Use of SUL-DUR and other drugs to treat these types of infections are discussed. In conclusion, SUL-DUR is a promising therapy for serious infections caused by CRAB.

Principles and Practice of Antimicrobial Stewardship Program Resource Allocation.

Antimicrobial Stewardship Programs (ASP) improve individual patient outcomes and clinical care processes while reducing antimicrobial-associated adverse events, optimizing operational priorities, and providing institutional cost savings. ASP composition, resources required, and priority focuses are influenced by myriad factors. Despite robust evidence and broad national support, individual ASPs still face challenges in obtaining appropriate resources. Though understanding the current landscape of ASP resource allocation, factors influencing staffing needs, and strategies required to obtain desired resources is important, acceptance of recommended staffing levels and appropriate ASP resource allocation are much needed to facilitate ASP sustainability and growth across the complex and diverse health care continuum.

Challenges and Opportunities in Antimicrobial Stewardship among Hematopoietic Stem Cell Transplant and Oncology Patients.

Antimicrobial stewardship programs play a critical role in optimizing the use of antimicrobials against pathogens in the era of growing multi-drug resistance. However, implementation of antimicrobial stewardship programs among the hematopoietic stem cell transplant and oncology populations has posed challenges due to multiple risk factors in the host populations and the infections that affect them. The consideration of underlying immunosuppression and a higher risk for poor outcomes have shaped therapeutic decisions for these patients. In this multidisciplinary perspective piece, we provide a summary of the current landscape of antimicrobial stewardship, unique challenges, and opportunities for unmet needs in these patient populations.

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.

Utility of triazole antifungal therapeutic drug monitoring: Insights from the Society of Infectious Diseases Pharmacists: Endorsed by the Mycoses Study Group Education and Research Consortium.

Triazole antifungals (i.e., fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole) are commonly used in clinical practice to prevent or treat invasive fungal infections. Most triazole antifungals require therapeutic drug monitoring (TDM) due to highly variable pharmacokinetics, known drug interactions, and established relationships between exposure and response. On behalf of the Society of Infectious Diseases Pharmacists (SIDP), this insight describes the pharmacokinetic principles and pharmacodynamic targets of commonly used triazole antifungals and provides the rationale for utility of TDM within each agent.

Safety and Effectiveness of High-Dose Cefazolin in Patients With High Body Weight: A Retrospective Cohort Study.

Background: Cefazolin is a commonly used antibiotic for the treatment of mild to severe infections. Despite the use of higher dose of cefazolin (3 g/dose) for surgical prophylaxis in patients with obesity, there is currently a paucity of data identifying the optimal dose to treat infections in this specific patient population. Methods: This was a multicenter, retrospective cohort study of patients who received cefazolin at weight-based (up to 9 g/day) or standard doses (up to 6 g/day) for the treatment of bacteremia or skin and soft tissue infection (SSTI). Study groups were stratified by body weight and cefazolin dose received. Primary outcome was the composite of treatment-emergent adverse events (TEAEs) and secondary outcome was treatment failure rate. Results: A total of 208 patients were included for study analysis. Fifty-nine patients had body weight >120 kg. Of these, 33 received high-dose cefazolin while 26 received standard doses. The remaining 149 patients had body weight of ≤120 kg and received standard doses. The occurrence of TEAEs did not differ across the 3 groups. The study also did not find any difference between the rate of treatment failure between groups. Conclusions: High-dose cefazolin (9 g/day) for the treatment of bacteremia or SSTIs in patients with high body weight was safe and well tolerated. Larger studies are needed to further explore the benefit of high-dose cefazolin in improving clinical outcomes.

Pharmacogenetic variability and the probability of site of action target attainment during tuberculosis meningitis treatment: A physiologically based pharmacokinetic modeling and simulations study.

OBJECTIVE AND METHODS: Our objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted. RESULTS: The rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing. CONCLUSION: In this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies.

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.