Risk of Acute Kidney Injury Based on Vancomycin Target Trough Attainment Strategy: Area-Under-the-Curve-Guided Bayesian Software, Nomogram, or Trough-Guided Dosing.

BACKGROUND: Guidelines support area-under-the-curve (AUC) monitoring for vancomycin dosing which may lower overall doses and reduce acute kidney injury (AKI). OBJECTIVE: The aim of this study was to compare incidence of AKI across 3 vancomycin dosing modalities: AUC-targeted Bayesian pharmacokinetic software, AUC-targeted empiric dosing nomogram, and trough-guided dosing using clinical pharmacists' judgment. METHODS: This retrospective study included adult patients with a pharmacy dosing consult who received ≥1 dose of vancomycin and ≥1 serum vancomycin level documented between January 1, 2018, and December 31, 2019. Patients with baseline serum creatinine ≥2 mg/dL, weight ≥100 kg, receiving renal replacement therapy, AKI prior to vancomycin therapy, or vancomycin ordered only for surgical prophylaxis were excluded. The primary analysis was incidence of AKI adjusted for baseline serum creatinine, age, and intensive care unit admission. A secondary outcome was adjusted incidence of an abnormal trough value (<10 or >20 µg/mL). RESULTS: The study included 3459 encounters. Incidence of AKI was 21% for Bayesian software (n = 659), 22% for the nomogram (n = 303), and 32% for trough-guided dosing (n = 2497). Compared with trough-guided dosing, incidence of AKI was lower in the Bayesian (adjusted odds ratio [OR] = 0.72, 95% confidence interval [CI]: 0.58-0.89) and the nomogram (adjusted OR = 0.71, 95% CI: 0.53-0.95) groups. Compared with trough-guided dosing, abnormal trough values were less common in the Bayesian group (adjusted OR = 0.83, 95% CI: 0.69-0.98). CONCLUSION AND RELEVANCE: Study results suggest that use of AUC-guided Bayesian software reduces the incidence of AKI and abnormal trough values compared with trough-guided dosing.

Remdesivir for Severe Coronavirus Disease 2019 (COVID-19) Versus a Cohort Receiving Standard of Care.

BACKGROUND: We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care. METHODS: GS-US-540-5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540-5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality. RESULTS: After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio [aOR] 2.03: 95% confidence interval [CI]: 1.34-3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22-.68, P = .001). CONCLUSIONS: In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19. CLINICAL TRIALS REGISTRATION: NCT04292899 and EUPAS34303.

Treatment of Coronavirus Disease 2019 (COVID-19) Patients with Convalescent Plasma.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has spread globally, and no proven treatments are available. Convalescent plasma therapy has been used with varying degrees of success to treat severe microbial infections for >100 years. Patients (n = 25) with severe and/or life-threatening COVID-19 disease were enrolled at the Houston Methodist hospitals from March 28, 2020, to April 14, 2020. Patients were transfused with convalescent plasma, obtained from donors with confirmed severe acute respiratory syndrome coronavirus 2 infection who had recovered. The primary study outcome was safety, and the secondary outcome was clinical status at day 14 after transfusion. Clinical improvement was assessed on the basis of a modified World Health Organization six-point ordinal scale and laboratory parameters. Viral genome sequencing was performed on donor and recipient strains. At day 7 after transfusion with convalescent plasma, nine patients had at least a one-point improvement in clinical scale, and seven of those were discharged. By day 14 after transfusion, 19 (76%) patients had at least a one-point improvement in clinical status, and 11 were discharged. No adverse events as a result of plasma transfusion were observed. Whole genome sequencing data did not identify a strain genotype-disease severity correlation. The data indicate that administration of convalescent plasma is a safe treatment option for those with severe COVID-19 disease.

Role of Rapid Diagnostics in Diagnosis and Management of Patients With Sepsis.

Delayed administration of active anti-infective therapy is associated with increased rates of adverse events, mortality, and costs among sepsis patients. Inherent limitations of conventional culture identification methods and the lengthy turnaround time of antimicrobial susceptibility testing are significant barriers to the timely delivery of life-saving therapy, particularly among antibiotic-resistant infections. Culture-independent diagnostic techniques that detect pathogens and antimicrobial resistance genes within clinical samples present a tremendous benefit to timely diagnosis and management of patients. Improved outcomes for rapid intervention with rapid diagnostics have been documented and include decreased mortality rates, decreased health care delivery costs, and faster delivery of appropriate therapeutics.

Impact of Chlorhexidine Bathing on Antimicrobial Utilization in Surgical Intensive Care Unit.

BACKGROUND: This secondary analysis compared antimicrobial utilization among surgical intensive care unit patients randomized to every other day chlorhexidine bathing (chlorhexidine) versus daily soap and water bathing (soap-and-water) using data from the CHlorhexidine Gluconate BATHing trial. MATERIALS AND METHODS: Antimicrobial utilization was quantified using defined daily dose (DDD)/100 patient-days and agent-days/100 patient-days for systemic antimicrobials. Antivirals (except oseltamivir), antiparasitics, and prophylaxis agents were excluded. The 2018 anatomic therapeutic chemical/DDD index was used to calculate DDD. Agent-days were calculated as the sum of calendar days where antimicrobials were administered. Patient-days were defined as time patients were at risk for health care-acquired infections plus up to 14 d. Primary analyses were conducted using linear regression adjusted for baseline Acute Physiology and Chronic Health Evaluation II scores. RESULTS: Of 325 CHlorhexidine Gluconate BATHing trial patients, 312 (157 in soap-and-water and 155 in chlorhexidine) were included. The median (interquartile range) of total antimicrobial DDD/100 patient-days was 135.4 (75.2-231.8) for soap-and-water and 129.9 (49.2-215.3) for chlorhexidine. The median (interquartile range) of total antimicrobial agent-days/100 patient-days was 155.6 (83.3-243.2) for soap-and-water and 146.7 (66.7-217.4) for chlorhexidine. After adjusting for Acute Physiology and Chronic Health Evaluation II scores, chlorhexidine bathing was associated with a nonsignificant reduction in total antimicrobial DDD/100 patient-days (-3.9; 95% confidence interval, -33.9 to 26.1; P = 0.80) and total antimicrobial agent-days/100 patient-days (-10.3; 95% confidence interval, -34.7 to 14.1; P = 0.41). CONCLUSIONS: Compared with daily soap and water bathing, every other day chlorhexidine bathing did not significantly reduce total antimicrobial utilization in surgical intensive care unit patients.

Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections.

Current immunosuppression regimens in organ transplantation primarily inhibit T cells. However, T cells are also critical in protective immunity, especially in immune-compromised patients. In this study, we examined the association of T cell dysfunction, as marked by expression of T cell exhaustion molecules, and posttransplant infections in a cohort of liver transplant patients. We focused on Programmed Death 1 (PD-1) and T cell Ig- and mucin-domain molecule 3 (Tim-3), which are potent co-inhibitory receptors, and their persistent expression often leads to T cell dysfunction and compromised protective immunity. We found that patients with the highest expression of PD-1 +Tim-3+ T cells in the memory compartment before transplantation had increased incidence of infections after liver transplantation, especially within the first 90 days. Longitudinal analysis in the first year showed a strong association between variability of PD-1 and Tim-3 expression by T cells and infectious episodes in transplant patients. Furthermore, T cells that expressed PD-1 and Tim-3 had a significantly reduced capacity in producing interferon (IFN)-γ in vitro, and this reduced IFN-γ production could be partially reversed by blocking PD-1 and Tim-3. Interestingly, the percentage of Foxp3+ regulatory T cells in liver transplant patients was stable in the study period. We concluded that the functional status of T cells before and after liver transplantation, as shown by PD-1 and Tim-3 expression, may be valuable in prognosis and management of posttransplant infections.

Postoperative antimicrobials after lung transplantation and the development of multidrug-resistant bacterial and Clostridium difficile infections: an analysis of 500 non-cystic fibrosis lung transplant patients.

BACKGROUND: Broad-spectrum antimicrobials are given prophylactically post-transplant, although these agents are a risk factor for multidrug-resistant (MDR) infections and Clostridium difficile infection (CDI). This study aimed to determine whether an association exists between the duration of antimicrobials given early post-transplant and the development of MDR infections or CDI. METHODS: A single-center retrospective analysis was performed on lung transplants from September 2009 to August 2014. Patients were excluded for cystic fibrosis (CF) or postoperative survival less than 30 d. Qualifying infections were defined as any new positive MDR bacterial culture or C. difficile assay from postoperative day 7-90 d after a broad-spectrum antimicrobial. RESULTS: A total of 500 patients, 61% male, were identified, median age of 62 yr. MDR infections occurred in 169 (34%) and CDI in 31 (6%). Non-ICU days were associated with a decreased risk of MDR/CDI (OR 0.891, p = 0.0002), and duration of Gram-positive antimicrobials (OR 1.073, p = 0.0219) was associated with an increased risk. CONCLUSIONS: One-third (34%) of non-CF lung transplants develop MDR infections and 6% develop CDI within 90 d of postoperative antimicrobials. The duration of Gram-positive antimicrobials may increase the risk of MDR/CDI, while early transfer from the ICU may have a protective effect.

Review of rapid diagnostic tests used by antimicrobial stewardship programs.

Rapid microbiologic tests provide opportunities for antimicrobial stewardship programs to improve antimicrobial use and clinical and economic outcomes. Standard techniques for identification of organisms require at least 48-72 hours for final results, compared with rapid diagnostic tests that provide final organism identification within hours of growth. Importantly, rapid microbiologic tests are considered "game changers" and represent a significant advancement in the management of infectious diseases. This review focuses on currently available rapid diagnostic tests and, importantly, the impact of rapid testing in combination with antimicrobial stewardship on patient outcomes.

PBP2a mutations causing high-level Ceftaroline resistance in clinical methicillin-resistant Staphylococcus aureus isolates.

Ceftaroline is the first member of a novel class of cephalosporins approved for use in the United States. Although prior studies have identified eight ceftaroline-resistant methicillin-resistant Staphylococcus aureus (MRSA) isolates in Europe and Asia with MICs ranging from 4 to 8 mg/liter, high-level resistance to ceftaroline (>32 mg/liter) has not been described in MRSA strains isolated in the United States. We isolated a ceftaroline-resistant (MIC > 32 mg/liter) MRSA strain from the blood of a cystic fibrosis patient and five MRSA strains from the respiratory tract of this patient. Whole-genome sequencing identified two amino acid-altering mutations uniquely present in the ceftaroline-binding pocket of the transpeptidase region of penicillin-binding protein 2a (PBP2a) in ceftaroline-resistant isolates. Biochemical analyses and the study of isogenic mutant strains confirmed that these changes caused ceftaroline resistance. Thus, we identified the molecular mechanism of ceftaroline resistance in the first MRSA strain with high-level ceftaroline resistance isolated in the United States.

Real-world Assessment of 2879 COVID-19 Patients Treated With Monoclonal Antibody Therapy: A Propensity Score-Matched Cohort Study.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally and cause significant morbidity and mortality. Antispike protein monoclonal antibody (mAb) therapy has been shown to prevent progression to severe coronavirus disease 2019 (COVID-19). The objective of this study was to report the outcomes of high-risk, SARS-CoV-2-positive patients infused with 1 of the 3 mAb therapies available through Food and Drug Administration Emergency Use Authorization (EUA). Methods: A total of 4328 SARS-CoV-2-positive patients who satisfied EUA criteria for eligibility for receiving mAb therapy were infused with bamlanivimab or the combination therapies bamlanivimab-etesevimab or casirivimab-imdevimab from November 22, 2020, to May 31, 2021, at 6 infusion clinics and multiple emergency departments within the 8 Houston Methodist Hospitals in Houston, Texas. The primary outcome of hospital admission within 14 and 28 days postinfusion was assessed relative to a propensity score-matched cohort, matched based on age, race/ethnicity, median income by zip code, body mass index, comorbidities, and positive polymerase chain reaction date. Secondary outcomes included intensive care unit admission and mortality. Results: A total of 2879 infused patients and matched controls were included in the analysis, including 1718 patients infused with bamlanivimab, 346 patients infused with bamlanivimab-etesevimab, and 815 patients infused with casirivimab-imdevimab. Hospital admission and mortality rates were significantly decreased overall in mAb-infused patients relative to matched controls. Among the infused cohort, those who received casirivimab-imdevimab had a significantly decreased rate of admission relative to the other 2 mAb therapy groups (adjusted risk ratio,0.51; P=.001). Conclusions: Treatment with bamlanivimab, bamlanivimab-etesevimab, or casirivimab-imdevimab significantly decreased the number of patients who progressed to severe COVID-19 disease and required hospitalization.

Remdesivir Versus Standard-of-Care for Severe Coronavirus Disease 2019 Infection: An Analysis of 28-Day Mortality.

BACKGROUND: Remdesivir is approved by the US Food and Drug Administration for the treatment of patients hospitalized with coronavirus disease 2019 (COVID-19) and has been shown to shorten time to recovery and improve clinical outcomes in randomized trials. METHODS: This was the final day 28 comparative analysis of data from a phase 3, randomized, open-label study comparing 2 remdesivir regimens (5 vs 10 days, combined for this analysis [remdesivir cohort]) and a real-world retrospective longitudinal cohort study of patients receiving standard-of-care treatment (nonremdesivir cohort). Eligible patients, aged ≥18 years, had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), oxygen saturation ≤94% on room air or required supplemental oxygen, with pulmonary infiltrates. Propensity score matching (up to 1:10 ratio) was used to ensure comparable populations. We assessed day 14 clinical recovery (determined using a 7-point ordinal scale) and day 28 all-cause mortality (coprimary endpoints). RESULTS: A total of 368 (remdesivir) and 1399 (nonremdesivir) patients were included in the matched analysis. The day 14 clinical recovery rate was significantly higher among the remdesivir versus the nonremdesivir cohort (65.2% vs 57.1%; odds ratio [OR], 1.49; 95% confidence interval [CI], 1.16-1.90; P = 0.002). The day 28 mortality rate was significantly lower in the remdesivir cohort versus the nonremdesivir cohort (12.0% vs 16.2%; OR, 0.67; 95% CI, 0.47-.95; P = .03). CONCLUSIONS: Remdesivir was associated with significantly higher rates of day 14 clinical recovery, and lower day 28 mortality, compared with standard-of-care treatment in hospitalized patients with COVID-19. These data, taken together, support the use of remdesivir to improve clinical recovery and decrease mortality from SARS-CoV-2 infection.

Treatment of COVID-19 Patients with Convalescent Plasma in Houston, Texas.

BACKGROUND: COVID-19 disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally, and no proven treatments are available. Convalescent plasma therapy has been used with varying degrees of success to treat severe microbial infections for more than 100 years. METHODS: Patients (n=25) with severe and/or life-threatening COVID-19 disease were enrolled at the Houston Methodist hospitals from March 28 to April 14, 2020. Patients were transfused with convalescent plasma obtained from donors with confirmed SARS-CoV-2 infection and had been symptom free for 14 days. The primary study outcome was safety, and the secondary outcome was clinical status at day 14 post-transfusion. Clinical improvement was assessed based on a modified World Health Organization 6-point ordinal scale and laboratory parameters. Viral genome sequencing was performed on donor and recipient strains. RESULTS: At baseline, all patients were receiving supportive care, including anti-inflammatory and anti-viral treatments, and all patients were on oxygen support. At day 7 post-transfusion with convalescent plasma, nine patients had at least a 1-point improvement in clinical scale, and seven of those were discharged. By day 14 post-transfusion, 19 (76%) patients had at least a 1-point improvement in clinical status and 11 were discharged. No adverse events as a result of plasma transfusion were observed. The whole genome sequencing data did not identify a strain genotype-disease severity correlation. CONCLUSIONS: The data indicate that administration of convalescent plasma is a safe treatment option for those with severe COVID-19 disease. Randomized, controlled trials are needed to determine its efficacy.

Real-time Communication With Health Care Providers Through an Online Respiratory Pathogen Laboratory Report.

We implemented a real-time report to distribute respiratory pathogen data for our 8-hospital system to anyone with an Internet connection and a web browser. Real-time access to accurate regional laboratory observation data during an epidemic influenza season can guide diagnostic and therapeutic strategies.

The Role of an Antimicrobial Stewardship Team in the Use of Rapid Diagnostic Testing in Acute Care: An Official Position Statement of the Society of Infectious Diseases Pharmacists.

Rapid diagnostic technologies can assist Antimicrobial Stewardship Programs (ASPs) in achieving the goals of reducing unnecessary antimicrobial exposure and optimizing patient care. The Society of Infectious Diseases Pharmacists supports all members of the ASP team as essential components of optimal use of these technologies for management of antibiotic prescribing and cost-reduction strategies. Infect Control Hosp Epidemiol 2018;39:473-475.

Significant Publications on Infectious Diseases Pharmacotherapy in 2016.

PURPOSE: This is a summary of the most important articles on infectious diseases (ID) pharmacotherapy published in peer-reviewed literature in 2016 as selected by clinical pharmacists with ID expertise. SUMMARY: The Houston Infectious Diseases Network (HIDN) was asked to identify articles published in peer-reviewed literature in 2016 that were believed to contribute significantly to ID pharmacotherapy, including human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). A list of 46 articles on general ID pharmacotherapy and 8 articles on HIV/AIDS were nominated. Members of the Society of Infectious Diseases Pharmacists (SIDP) were surveyed to select 10 general ID articles believed to have made a significant impact on general ID pharmacotherapy and 1 article most significant to HIV/AIDS pharmacotherapy. Of 445 SIDP members surveyed, 212 (47.6%) and 95 (21.3%) members voted for general ID pharmacotherapy- and HIV/AIDS-related articles, respectively. The 11 highest-ranked papers (10 general ID-related articles and 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the large number of ID-related articles published each year, it can be challenging to stay current with the most relevant ID publications. This review of significant publications in 2016 may provide a starting point for that process.

Significant publications on infectious diseases pharmacotherapy in 2015.

PURPOSE: The most important articles on infectious diseases (ID) pharmacotherapy published in the peer-reviewed literature in 2015, as nominated and selected by panels of pharmacists and others with ID expertise, are summarized. SUMMARY: Members of the Houston Infectious Diseases Network were asked to nominate articles published in prominent peer-reviewed journals in 2015 that were thought to have a major impact in the field of ID pharmacotherapy. A list of 55 nominated articles on general ID-related topics and 10 articles specifically related to human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) was compiled. In a national online survey, members of the Society of Infectious Diseases Pharmacists (SIDP) were asked to select from the list 10 general ID articles believed to have made a significant contribution to the field of ID pharmacotherapy and 1 article contributing to HIV/AIDS pharmacotherapy. Of the 361 SIDP members surveyed, 153 (42%) and 76 (21%) participated in the selection of general ID-related articles and HIV/AIDS-related articles, respectively. The 11 highest-ranked publications (10 general ID-related articles and 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the growing number of significant ID-related publications each year, it can be challenging to stay current with the literature. This review of important ID pharmacotherapy publications in 2015 may be helpful in identifying key articles and lessening this burden.

Clinical pathway for moderate to severe acute bacterial skin and skin structure infections from a US perspective: a roundtable discussion.

This article was written with the aim to establish a consensus clinical pathway for long-acting lipoglycopeptide antibiotics such as oritavancin (Orbactiv®) and dalbavancin (Dalvance®) for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Seven infectious diseases pharmacy specialists from a variety of facilities across the United States (US) participated in a roundtable discussion to consider the use of newer single-dose long-acting lipoglycopeptides, and integrate them into clinical pathways for ABSSSI. They identified two ways of treating with these drugs: first, to facilitate discharge from the hospital by switching from initial therapy (e.g., with intravenous (IV) vancomycin) and second, to avoid hospital admission altogether, since the product can be administered in several outpatient settings of care including the emergency department (ED), observation unit (OU) or outpatient infusion center. The participants used existing literature on classification and treatment of ABSSSI and their experience in the clinical setting as bases for their discussion and came to a consensus on the considerations for patient inclusion and exclusion as well as a pathway for outpatient treatment with long-acting lipoglycopeptides. As a result of the discussion, we concluded that the current treatment paradigm for ABSSSI is ripe for re-evaluation and reconfiguration in order to more closely align with the changing healthcare landscape. Hospital stakeholders are constantly searching for new strategies that can improve quality of care while simultaneously reducing overall expenses. The availability of single-dose long-acting lipoglycopeptides is an opportunity to opt for lower-cost outpatient treatment of appropriate ABSSSI patients. This article proposes the inclusion and exclusion considerations, along with a consensus treatment pathway, that could provide a solid foundation for facilities to construct and adapt their own effective clinical pathways for ABSSSI.

Integrating Rapid Diagnostics and Antimicrobial Stewardship in Two Community Hospitals Improved Process Measures and Antibiotic Adjustment Time.

OBJECTIVE To assess the impact of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) mass spectrometry for rapid pathogen identification directly from early-positive blood cultures coupled with an antimicrobial stewardship program (ASP) in two community hospitals. Process measures and outcomes prior and after implementation of MALDI-TOF/ASP were evaluated. DESIGN Multicenter retrospective study. SETTING Two community hospitals in a system setting, Houston Methodist (HM) Sugar Land Hospital (235 beds) or HM Willowbrook Hospital (241 beds). PATIENTS Patients ≥ 18 years of age with culture-proven Gram-negative bacteremia. INTERVENTION Blood cultures from both hospitals were sent to and processed at our central microbiology laboratory. Clinical pharmacists at respective hospitals were notified of pathogen ID and susceptibility results. RESULTS We evaluated 572 patients for possible inclusion. After pre-defined exclusion criteria, 151 patients were included in the pre-intervention group and 242 were included in the intervention group. After MALDI-TOF/ASP implementation, the mean identification time after culture positivity was significantly reduced from 32 hours (±16 hours) to 6.5 hours (±5.4 hours) (P<.001); mean time to susceptibility results was significantly reduced from 48 (±22) hours to 23 (±14) hours (P<.001); and time to therapy adjustment was significantly reduced from 75 (±59) hours to 30 (±30) hours (P<.001). Mean hospital costs per patient were $3,411 less in the intervention group compared with the pre-intervention group ($18,645 vs $15,234; P=.04). CONCLUSION This study is the first to analyze the impact of MALDI-TOF coupled with an ASP in a community hospital setting. Time to results significantly differed with the use of MALDI-TOF, and time to appropriate therapy was significantly improved with the addition of ASP.