Evaluation of Gram Stain-Guided Antibiotic Therapy for Methicillin-Resistant Staphylococcus aureus Pneumonia in Intensive Care Unit Patients.

Background: Despite high negative predictive values (NPVs) seen with methicillin-resistant Staphylococcus aureus (MRSA) nares polymerase chain reaction (PCR) assays, utilization of both respiratory sample Gram stain and MRSA nares PCR in patients with pneumonia may contribute to overuse of laboratory resources. The purpose of this study was to evaluate if a Gram stain demonstrating no Gram-positive organisms from a respiratory sample is sufficient to allow for de-escalation of vancomycin therapy. Methods: This single center study retrospectively identified intensive care unit (ICU) patients started on vancomycin for presumed pneumonia at University of Wisconsin (UW) Health in Madison, WI between August 2022 and March 2023. Patients with respiratory sample demonstrating no Gram-positives on Gram stain met inclusion criteria if the sample was ordered within 24 h of vancomycin initiation. The primary outcome was NPV of respiratory sample Gram stain demonstrating no Gram-positive organisms with respect to MRSA detection of the respiratory culture. Secondary outcomes included the NPV of combined MRSA nares PCR plus respiratory sample Gram stain, and difference in time to event in patients that had both a respiratory sample and MRSA nares PCR ordered. Results: A total of 370 patients were screened for study eligibility; of which 99 patients met inclusion criteria. NPV of respiratory sample Gram stain was 99% for MRSA culture. The combined NPV of respiratory sample Gram stain plus MRSA nares PCR was 98.9% for MRSA culture (n = 88). Respiratory sample was ordered 2.3 h faster compared to MRSA nares PCR (4.3 vs 6.6 h, P = .036). Respiratory sample Gram stain resulted 4.5 h faster compared to MRSA nares PCR (10.7 vs 15.2 h, P = .002). Conclusion: Respiratory sample Gram stains demonstrating no Gram-positive organisms may be used to de-escalate vancomycin and deprioritize the use of MRSA nares PCR.

A Scoping Review of Bacterial Resistance Among Inpatients Amidst the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic disrupted antimicrobial stewardship and infection prevention operations worldwide, raising concerns for an acceleration of antimicrobial resistance (AMR). Therefore, we aimed to define the scope of peer reviewed research comparing AMR in inpatient bacterial clinical cultures before and after the start of the COVID-19 pandemic. METHODS: We conducted a scoping review and searched PubMed, Scopus, and Web of Science through June 15, 2023. Our inclusion criteria were: (1) English language, (2) primary evidence, (3) peer-reviewed, (4) clinical culture data from humans, (5) AMR data for at least one bacterial order/species, (6) inpatient setting, (7) use of statistical testing to evaluate AMR data before and during the COVID-19 pandemic. Reviewers extracted country, study design, type of analysis, study period, setting & population, number of positive cultures or isolates, culture type(s), method of AMR analysis, organisms, and AMR results. Study results were organized by organism and antibiotic class or resistance mechanism. AMR results are also summarized by individual study and across all studies. RESULTS: In total, 4,805 articles were identified with 55 papers meeting inclusion criteria. Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus were the most commonly studied organisms. There were 464 bacterial AMR results across all studies with 82 (18%) increases, 71 (15%) decrease, and 311 (67%) no change results. CONCLUSION: The literature examining the impact of COVD-19 on AMR among inpatients is diverse with most results reflecting no change pre/post pandemic. Ongoing inquiry is needed into examine evolving patterns in AMR post COVID-19.

Finding value in novel antibiotics: How can infectious diseases adopt incremental cost-effectiveness to improve new antibiotic utilization?

Research and development of innovative antimicrobials is paramount to addressing the antimicrobial resistance threat. Although antimicrobial discovery and development has increased, difficulties have emerged in the pharmaceutical industry after market approval. In this minireview, we summarize clinical trial data on recently approved antibiotics, calculate incremental cost-effectiveness ratio (ICER) values, and explore ways to adapt ICER calculations to the limitations of antimicrobial clinical trial design. We provide a systematic review and analysis of randomized, controlled studies of antibiotics approved from 2014 - 2022 and extracted the relevant clinical data. Adapted-ICER (aICER) calculations were conducted using the primary condition-specific outcome that was reported in each study (percent mortality or percent cure rate). The literature search identified 18 studies for the 8 total antibiotics which met inclusion criteria and contained data required for aICER calculation. aICER values ranged from -$17,374 to $4,966 per percent mortality and -$43,931 to $2,529 per percent cure rate. With regards to mortality, ceftolozane/tazobactam and imipenem/cilastatin/relebactam proved cost efficacious, with aICER values of $4,965 per percent mortality and $1,955 per percent mortality respectively. Finding value in novel antibiotic agents is imperative to further justifying their development, and aICER values are the most common method of determining value in healthcare. The current outcomes of clinical trials are difficult to translate to aICER, which most effectively use Quality-Adjusted Life Years (QALY) as the quality standard in other fields such as oncology. Future antimicrobial trials should consider introducing methods of assessing measures of health gain such as QALY to better translate the value of novel antimicrobials in healthcare.

Resource Use and Financial Impact of Oral Step-Down Therapy for Resistant Cytomegalovirus in Solid Organ Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV) infections are common opportunistic infections in solid organ transplants (SOT) with increased health care resource USE and costs. Costs are further increased with ganciclovir-resistance (GR). This study aimed to evaluate the real-world impact of conversion to oral step-down therapy on duration of foscarnet and hospital length of stay (LOS) for treatment of GR-CMV infections in SOT. METHODS: This study included adult recipients of kidney or lung transplants who received foscarnet for genotypically documented GR-CMV while admitted at the University of Wisconsin Hospital from October 1, 2015, to January 31, 2022. Patients in the oral step-down group were converted from standard of care (SOC; foscarnet) to maribavir or letermovir; patients in the historical control group were treated with SOC. RESULTS: Twenty-six patients met the inclusion criteria: 5 in the intervention group and 21 in the SOC group. The median viral load at foscarnet initiation was 11,435 IU/mL. Patients who received oral step-down conversion had shorter mean foscarnet duration than those who received SOC (7 ± 4 vs 37 ± 25 days, P = .017). Mean hospital LOS in the oral step-down group (16 ± 3 days) was shorter than the SOC group (33 ± 21 days; P < .001). In the SOC group, 9 patients lost their graft, and 9 patients died; 2 deaths were attributed to CMV. There were 2 deaths in the oral step-down group, neither of which was attributed to CMV. CONCLUSION AND RELEVANCE: In this real-world case series of patients receiving treatment for GR-CMV infection, oral step-down conversion decreased foscarnet therapy duration and hospital LOS. Future studies are needed to evaluate better the effect of oral step-down in treating GR-CMV infection on treatment duration and cost-savings.

Understanding clinical implementation coordinators' experiences in deploying evidence-based interventions.

PURPOSE: The fluoroquinolone restriction for the prevention of Clostridioides difficile infection (FIRST) trial is a multisite clinical study in which sites carry out a preauthorization process via electronic health record-based best-practice alert (BPA) to optimize the use of fluoroquinolone antibiotics in acute care settings. Our research team worked closely with clinical implementation coordinators to facilitate the dissemination and implementation of this evidence-based intervention. Clinical implementation coordinators within the antibiotic stewardship team (AST) played a pivotal role in the implementation process; however, considerable research is needed to further understand their role. In this study, we aimed to (1) describe the roles and responsibilities of clinical implementation coordinators within ASTs and (2) identify facilitators and barriers coordinators experienced within the implementation process. METHODS: We conducted a directed content analysis of semistructured interviews, implementation diaries, and check-in meetings utilizing the conceptual framework of middle managers' roles in innovation implementation in healthcare from Urquhart et al. RESULTS: Clinical implementation coordinators performed a variety of roles vital to the implementation's success, including gathering and compiling information for BPA design, preparing staff, organizing meetings, connecting relevant stakeholders, evaluating clinical efficacy, and participating in the innovation as clinicians. Coordinators identified organizational staffing models and COVID-19 interruptions as the main barriers. Facilitators included AST empowerment, positive relationships with staff and oversight/governance committees, and using diverse implementation strategies. CONCLUSION: When implementing healthcare innovations, clinical implementation coordinators facilitated the implementation process through their roles and responsibilities and acted as strategic partners in improving the adoption and sustainability of a fluoroquinolone preauthorization protocol.

Diagnostic testing and antibiotic utilization among inpatients evaluated for coronavirus disease 2019 (COVID-19) pneumonia.

We evaluated diagnostic test and antibiotic utilization among 252 patients from 11 US hospitals who were evaluated for coronavirus disease 2019 (COVID-19) pneumonia during the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) omicron variant pandemic wave. In our cohort, antibiotic use remained high (62%) among SARS-CoV-2-positive patients and even higher among those who underwent procalcitonin testing (68%).

A geospatial approach to identify patterns of antibiotic susceptibility at a neighborhood level in Wisconsin, United States.

The global threat of antimicrobial resistance (AMR) varies regionally. This study explores whether geospatial analysis and data visualization methods detect both clinically and statistically significant variations in antibiotic susceptibility rates at a neighborhood level. This observational multicenter geospatial study collected 10 years of patient-level antibiotic susceptibility data and patient addresses from three regionally distinct Wisconsin health systems (UW Health, Fort HealthCare, Marshfield Clinic Health System [MCHS]). We included the initial Escherichia coli isolate per patient per year per sample source with a patient address in Wisconsin (N = 100,176). Isolates from U.S. Census Block Groups with less than 30 isolates were excluded (n = 13,709), resulting in 86,467 E. coli isolates. The primary study outcomes were the results of Moran's I spatial autocorrelation analyses to quantify antibiotic susceptibility as spatially dispersed, randomly distributed, or clustered by a range of - 1 to + 1, and the detection of statistically significant local hot (high susceptibility) and cold spots (low susceptibility) for variations in antibiotic susceptibility by U.S. Census Block Group. UW Health isolates collected represented greater isolate geographic density (n = 36,279 E. coli, 389 = blocks, 2009-2018), compared to Fort HealthCare (n = 5110 isolates, 48 = blocks, 2012-2018) and MCHS (45,078 isolates, 480 blocks, 2009-2018). Choropleth maps enabled a spatial AMR data visualization. A positive spatially-clustered pattern was identified from the UW Health data for ciprofloxacin (Moran's I = 0.096, p = 0.005) and trimethoprim/sulfamethoxazole susceptibility (Moran's I = 0.180, p < 0.001). Fort HealthCare and MCHS distributions were likely random. At the local level, we identified hot and cold spots at all three health systems (90%, 95%, and 99% CIs). AMR spatial clustering was observed in urban areas but not rural areas. Unique identification of AMR hot spots at the Block Group level provides a foundation for future analyses and hypotheses. Clinically meaningful differences in AMR could inform clinical decision support tools and warrants further investigation for informing therapy options.

Neutropenic Fever-Associated Admissions Among Patients With Solid Tumors Receiving Chemotherapy During the COVID-19 Pandemic.

This cohort study examines the rates of neutropenic fever­associated admissions and outpatient antibiotic use among patients with cancer receiving chemotherapy before and during the COVID-19 pandemic.

Nirmatrelvir-ritonavir treatment of COVID-19 in a high-risk patient population: A retrospective observational study.

Background: Coronavirus disease 2019 (COVID-19) is a highly contagious, airborne viral infection that can infect anyone. Those with certain underlying conditions may be at higher risk for infection to develop into a severe disease requiring hospitalization. This report summarizes use of nirmatrelvir-ritonavir for the treatment of COVID-19 in high-risk patients at a single academic medical center through a pharmacist delegation protocol and demonstrates real-world efficacy and safety of treatment. Methods: This retrospective, single-center, observational study analyzed all patients who received nirmatrelvir-ritonavir ordered by a clinical pharmacist for treatment of COVID-19 infection. The primary outcomes were safety and efficacy of nirmatrelvir-ritonavir. Safety was evaluated by analyzing drug interaction management and adverse events. Efficacy was evaluated through hospitalization and death within 28 days of nirmatrelvir-ritonavir use. Results: Sixty patients were eligible for inclusion. No patients were hospitalized or died within 28 days after initiation of nirmatrelvir-ritonavir. Pharmacists identified 101 drug interactions with 60% considered clinically significant, requiring modification of home medications. Adverse outcomes associated with the use of nirmatrelvir-ritonavir were reported in 13 patients (21.7%). Conclusions: A comprehensive program to mitigate drug interactions and prescribe nirmatrelvir-ritonavir ensured timely access to COVID-19 therapy, which may be associated with the prevention of hospitalization and death.

CMV antiviral stewardship: navigating obstacles to facilitate target attainment.

PURPOSE OF REVIEW: Despite the availability of potent antivirals, consensus guidelines and decades of research, cytomegalovirus (CMV) continues to be associated with negative outcomes after solid organ transplant. This has been attributed to postprophylaxis CMV infection and a lack of development of CMV-specific cell mediated immunity (CMI). A shift from a focus on antiviral prevention to a focus on CMI target attainment is needed to improve CMV outcomes after transplantation. RECENT FINDINGS: There are many obstacles to CMI target attainment. Antiviral stewardship programs (AVS) have been employed to improve patient outcomes through appropriate antiviral use, reduction of unnecessary exposure and resistance mitigation. By focusing on the patient's unique substrate of conglomerate risk factors and addressing these factors specifically with evidenced based methodology, the AVS can address these obstacles, increasing rates of CMI and subsequently reducing risk of future CMV infection and negative outcomes. SUMMARY: With its multidisciplinary composition utilizing decades of experience from antimicrobial stewardship principles and practices, the AVS is uniquely poised to facilitate the shift from a focus on prevention to CMI target attainment and be the supporting pillar for the frontline transplant clinician caring for transplant patients with CMV.

Maribavir for the Management of Cytomegalovirus in Adult Transplant Recipients: A Review of the Literature and Practical Considerations.

OBJECTIVE: To review the efficacy and safety of maribavir for management of cytomegalovirus (CMV) in solid organ transplant recipients. DATA SOURCES: A literature search of PubMed and the Cochrane Controlled Trials Register (1960 to early July 2022) was performed using the following search terms: maribavir, 1263W94, and cytomegalovirus. STUDY SELECTION AND DATA EXTRACTION: All relevant English-language studies were reviewed and considered, with a focus on phase 3 trials. DATA SYNTHESIS: Maribavir, an orally available benzimidazole riboside with minimal adverse effects, was originally studied for universal prophylaxis in phase 3 trials but failed to demonstrate noninferiority over placebo and oral ganciclovir. It was effective for preemptive treatment in a dose-finding Phase 2 study. Maribavir is FDA approved for treatment of refractory/resistant CMV infection based on improved response rate at 8 weeks compared with investigator-assigned therapy (IAT) when initiated at median viral loads less than approximately 10 000 IU/mL (55.7% vs 23.9%, P < 0.001). Recurrence after 8-week treatment for refractory/resistant CMV was high (maribavir 50% vs IAT 39%). Significant drug interactions exist and must be managed by a pharmacotherapy expert to prevent harm. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The addition of maribavir to the antiviral armamentarium should improve the management of refractory/resistant CMV, allowing early transition from toxic, high-cost, intravenous agents such as foscarnet and outpatient management. Optimal timing of initiation, duration, and potential alternative uses are unclear. CONCLUSION: Future studies are needed to fully elucidate the role of maribavir in the management of CMV after transplant.

The impact of coronavirus disease 2019 (COVID-19) on the antimicrobial stewardship pharmacist workforce: A multicenter survey.

Objective: The coronavirus disease 2019 (COVID-19) pandemic has required healthcare systems and hospitals to rapidly modify standard practice, including antimicrobial stewardship services. Our study examines the impact of COVID-19 on the antimicrobial stewardship pharmacist. Design: A survey was distributed nationally to all healthcare improvement company members. Participants: Pharmacist participants were mostly leaders of antimicrobial stewardship programs distributed evenly across the United States and representing urban, suburban, and rural health-system practice sites. Results: Participants reported relative increases in time spent completing tasks related to medication access and preauthorization (300%; P = .018) and administrative meeting time (34%; P = .067) during the COVID-19 pandemic compared to before the pandemic. Time spent rounding, making interventions, performing pharmacokinetic services, and medication reconciliation decreased. Conclusion: A shift away from clinical activities may negatively affect the utilization of antimicrobials.

ß-Lactam Therapeutic Drug Monitoring in Critically Ill Patients: Weighing the Challenges and Opportunities to Assess Clinical Value.

OBJECTIVE: ß-lactams are the cornerstone of empiric and targeted antibiotic therapy for critically ill patients. Recently, there have been calls to use ß-lactam therapeutic drug monitoring (TDM) within 24-48 hours after the initiation of therapy in critically ill patients. In this article, we review the dynamic physiology of critically ill patients, ß-lactam dose response in critically ill patients, the impact of pathogen minimum inhibitory concentration (MIC) on ß-lactam TDM, and pharmacokinetics in critically ill patients. Additionally, we highlight available clinical data to better inform ß-lactam TDM for critically ill patients. DATA SOURCES: We retrospectively analyzed patients admitted for sepsis or septic shock at a single academic medical center who were treated with ß-lactam antibiotics. STUDY SELECTION: Indexed studies in PubMed in English language were selected for review on topics relative to critical care physiology, ß-lactams, pharmacokinetics/pharmacodynamics, TDM, and antibiotic susceptibility. DATA EXTRACTION: We reviewed potentially related studies on ß-lactams and TDM and summarized their design, patients, and results. This is a synthetic, nonsystematic, review. DATA SYNTHESIS: In the retrospective analysis of patients treated with ß-lactam antibiotics, approximately one-third of patients received less than 48 hours of ß-lactam therapy. Of those who continued beyond 48 hours, only 13.7% had patient-specific factors (augmented renal clearance, fluid overload, morbid obesity, and/or surgical drain), suggesting a potential benefit of ß-lactam TDM. CONCLUSIONS: These data indicate that a strategy of comprehensive ß-lactam TDM for critically ill patients is unwarranted as it has not been shown yet to improve patient-oriented outcomes. This review demonstrates that ß-lactam TDM in the ICU, while laudable, layers ambiguous ß-lactam exposure thresholds upon uncertain/unknown MIC data within a dynamic, unpredictable patient population for whom TDM results will not be available fast enough to significantly affect care. Judicious, targeted TDM for those with risk factors for ß-lactam over- or underexposure is a better approach but requires further study. Clinically, choosing the correct antibiotic and dosing ß-lactams aggressively, which have a wide therapeutic index, to overcome critical illness factors appears to give critically ill patients the best likelihood of survival.

Telestewardship programs support clinical care and improve fiscal outcomes across the continuum through partnership between hospitals and health systems: A systematic review.

PURPOSE: A systematic review was performed to determine if remote stewardship (telestewardship) provides clinical and fiscal benefit and is a feasible alternative to local stewardship programs. SUMMARY: Antibiotic resistance is an increasingly important national and global threat. US regulators have made antimicrobial stewardship programs a condition of participation in federally funded healthcare programs, and stewardship programs are surveyed during accreditation visits. Small and rural hospitals are at risk for stewardship noncompliance because lack of resources limits comprehensive stewardship program implementation. Remote stewardship programs are established to remedy this area of partial compliance. To characterize the impact of remote stewardship on selected clinical and fiscal outcomes, PubMed was searched for studies involving telestewardship that reported data on antimicrobial utilization, patient length of stay, mortality, bacterial susceptibility, hospital-acquired Clostridioides difficile infection (HA-CDI), and/or antimicrobial costs. A systematic approach was used to screen study titles, abstracts, and content and data extracted. Study quality was analyzed using Cochrane risk-of-bias assessment tools. Fourteen studies were included in the final review. Collectively, the antimicrobial utilization data was positive, with utilization of targeted antimicrobials decreasing after telestewardship implementation. Mixed (both positive and neutral) results were found for patient length of stay, mortality, and HA-CDI rates. Fiscal outcomes were consistently positive. CONCLUSION: Based on the reviewed evidence, remote antimicrobial stewardship programs may aid in the more judicious use of antimicrobials by decreasing utilization rates. More studies are needed to clarify patient-oriented outcomes. Telestewardship has positive effects in terms of cost savings, although savings may be offset by the structure of the program.

Implementation of telehealth antimicrobial stewardship through partnership of an academic medical center and a community hospital.

PURPOSE: Small community hospitals often lack the human, financial, and technological resources necessary to implement and maintain successful antimicrobial stewardship programs now required by national regulatory and accrediting bodies. Creative solutions are needed to address this problem. SUMMARY: A 3-stage, quasi-experimental study including patients receiving antibiotics for pneumonia, skin and soft tissue infections, and urinary tract infections at a community hospital in Wisconsin from June 2013 to December 2015 was conducted. Remote telehealth prospective audit and feedback, guideline and order set management, and staff education targeting pharmacists, nurses, and physicians were provided during the 7-month intervention phase; these services were then removed for the postintervention period. Antimicrobial utilization (days of therapy [DOT] per 1,000 patient-days), hospital length of stay, and readmission and 30-day mortality rates were assessed to determine the impact of telehealth services on these outcomes. During the preintervention (baseline), intervention, and postintervention periods, 1,037 patients received antibiotics for the targeted infectious disease conditions. Patient demographics and rates of infectious disease conditions were similar among the different periods. Telehealth antimicrobial stewardship reduced broad-spectrum antibiotic use, including use of imipenem (from 83 to 31 DOT, P < 0.001), levofloxacin (from 123 to 99 DOT, P < 0.001), and vancomycin (from 104 to 85 DOT, P < 0.001), compared to utilization during the baseline period; mean (SD) length of stay also decreased (from 4.6 [2.8] days to 4.2 [2.6] days, P = 0.02). After nonrenewal of telehealth stewardship, vancomycin and piperacillin/tazobactam usage returned to or exceeded baseline levels. CONCLUSION: The partnership between an academic medical center and a small community hospital improved antimicrobial utilization and clinical outcomes. Successful telehealth antimicrobial stewardship models should be explored further as a means to provide optimal patient care.

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.