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.

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.

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.

Vancomycin Advanced Therapeutic Drug Monitoring: Exercise in Futility or Virtuous Endeavor to Improve Drug Efficacy and Safety?

Vancomycin is commonly prescribed to hospitalized patients. Decades of pharmacokinetic/pharmacodynamic research culminated in recommendations to monitor the ratio of the area under the concentration-time curve (AUC) to the minimum inhibitory concentration in order to optimize vancomycin exposure and minimize toxicity in the revised 2020 guidelines. These guideline recommendations are based on limited data without high-quality evidence and limitations in strength. Despite considerable effort placed on vancomycin therapeutic drug monitoring (TDM), clinicians should recognize that the majority of vancomycin use is empiric. Most patients prescribed empiric vancomycin do not require it beyond a few days. For these patients, AUC determinations during the initial days of vancomycin exposure are futile. This added workload may detract from high-level patient care activities. Loading doses likely achieve AUC targets, so AUC monitoring after a loading dose is largely unnecessary for broad application. The excessive vancomycin TDM for decades has been propagated with limitations in evidence, and it should raise caution on contemporary vancomycin TDM recommendations.

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

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

Penicillin Allergy Evaluation Access: A National Survey.

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

Impact of Triazole Therapeutic Drug Monitoring Availability and Timing.

Therapeutic drug monitoring (TDM) is an established strategy to optimize antifungal therapy with certain triazoles. While established relationships exist between concentration and safety or efficacy, the impact of TDM timing on outcomes is unknown. We report clinical outcomes, including antifungal exposure and mortality, in patients receiving institutional versus reference laboratory TDM. The availability of in-house triazole assays reduced the time to drug concentration result (12 versus 68 h; P < 0.001) and time to achieve therapeutic serum concentrations (10 versus 31 days; P < 0.001). Subtherapeutic concentrations were associated with higher patient mortality (32% versus 13.3%; P = 0.036).

Top 10 Myths Regarding the Diagnosis and Treatment of Cellulitis.

BACKGROUND: Cellulitis is commonly treated in the emergency department (ED). Patients who present with cellulitis incur significant health care costs and may be overtreated with antibiotics. The accurate diagnosis and treatment of cellulitis plays an important role in cost-effective, high-quality medical care, as well as appropriate antibiotic utilization. OBJECTIVE: We aim to describe common fallacies regarding cellulitis. We present 10 myths that result in misdiagnosis, overtreatment, or inappropriate empiric management of cellulitis. Clinical presentation, including swelling and redness, is explored in depth, along with incidence of community-acquired methicillin-resistance Staphylococcus aureus, management of tick bites, and effective antibiotic therapy for cellulitis. DISCUSSION: Patients are often treated for cellulitis unnecessarily or inappropriately. Awareness of these myths will help guide providers in clinical decision making in order to effectively tailor treatment for these infections. CONCLUSIONS: Cellulitis is not as simple as it might seem, and is commonly misdiagnosed in the ED. Noninfectious causes of local symptoms, including lymphedema, venous stasis, and deep vein thrombosis need to be considered. Cellulitis should be treated with empiric antimicrobial therapy based on patient risk factors and regional susceptibility patterns. This review will assist providers in managing cellulitis and avoiding treatment errors that lead to high costs, unwanted side effects for patients, and overuse of antibiotics.

Use of electronic health records and clinical decision support systems for antimicrobial stewardship.

Electronic health records (EHRs) and clinical decision support systems (CDSSs) have the potential to enhance antimicrobial stewardship. Numerous EHRs and CDSSs are available and have the potential to enable all clinicians and antimicrobial stewardship programs (ASPs) to more efficiently review pharmacy, microbiology, and clinical data. Literature evaluating the impact of EHRs and CDSSs on patient outcomes is lacking, although EHRs with integrated CDSSs have demonstrated improvements in clinical and economic outcomes. Both technologies can be used to enhance existing ASPs and their implementation of core ASP strategies. Resolution of administrative, legal, and technical issues will enhance the acceptance and impact of these systems. EHR systems will increase in value when manufacturers include integrated ASP tools and CDSSs that do not require extensive commitment of information technology resources. Further research is needed to determine the true impact of current systems on ASP and the ultimate goal of improved patient outcomes through optimized antimicrobial use.

Daptomycin dosing based on ideal body weight versus actual body weight: comparison of clinical outcomes.

Daptomycin use at our institution changed to ideal body weight dosing based on a published analysis of pharmacokinetic-pharmacodynamic efficacy target attainment, bacterial ecology, and a desire to reduce drug toxicity. The current study compared outcomes between actual body weight and ideal body weight dosing of daptomycin before and after this intervention. In the evaluable group, 69 patients received doses based on actual body weight and 48 patients received doses based on ideal body weight. Patients were treated for documented Enterococcus species, Staphylococcus aureus, or coagulase-negative Staphylococcus infections, including bloodstream, intraabdominal, skin and soft tissue, urinary, and bone. There was no statistically significant difference in clinical success between the groups (88.9% for actual body weight compared to 89.1% for ideal body weight, P = 0.97). After we adjusted for gender, age, body mass index, concomitant 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, infection type, and organism type, clinical success rates remained similar between groups (adjusted odds ratio of 0.68 in favor of actual body weight, 95% confidence interval [CI] of 0.13 to 3.55). Microbiological outcomes, length of stay, mortality, and adverse effects were also similar between groups. Further studies are warranted to confirm that ideal body weight dosing provides similar outcomes to actual body weight dosing for all patients and types of infections and organisms.

A scoping review of bacterial resistance among inpatients amidst the COVID-19 pandemic.

OBJECTIVES: 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 15 June 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 and population, number of positive cultures or isolates, culture type(s), method of AMR analysis, organisms, and AMR results. Study results were organised by organism and antibiotic class or resistance mechanism. AMR results are also summarised by individual study and across all studies. RESULTS: In total, 4805 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%) increase, 71 (15%) decrease, and 311 (67%) no change results. CONCLUSIONS: The literature examining the impact of COVID-19 on AMR among inpatients is diverse with most results reflecting no change pre/post pandemic. Ongoing inquiry is needed into 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%).

The "epic" challenge of optimizing antimicrobial stewardship: the role of electronic medical records and technology.

Antimicrobial stewardship programs (ASPs) are established means for institutions to improve patient outcomes while reducing the emergence of resistant bacteria. With the increased adoption and evolution of electronic medical records (EMRs), there is a need to assimilate the tools of ASPs into EMRs, using decision support and feedback. Third-party software vendors provide the mainstay for integration of individual institutional EMR and ASP efforts. Epic is the leading implementer of EMR technology in the United States. A collaboration of physicians and pharmacists are working closely with Epic to provide a more comprehensive platform of ASP tools that may be institutionally individualized. We review the historical relationship between ASPs and the EMR, cite examples of Epic stewardship tools from 3 academic medical centers' ASPs, discuss limitations of these Epic tools, and conclude with the current process in evolution to integrate ASP tools and decision support capacities directly into Epic's EMR.