The Penn Medicine COVID-19 Therapeutics Committee-Reflections on a Model for Rapid Evidence Review and Dynamic Practice Recommendations During a Public Health Emergency.

The Penn Medicine COVID-19 Therapeutics Committee-an interspecialty, clinician-pharmacist, and specialist-front line primary care collaboration-has served as a forum for rapid evidence review and the production of dynamic practice recommendations during the 3-year coronavirus disease 2019 public health emergency. We describe the process by which the committee went about its work and how it navigated specific challenging scenarios. Our target audiences are clinicians, hospital leaders, public health officials, and researchers invested in preparedness for inevitable future threats. Our objectives are to discuss the logistics and challenges of forming an effective committee, undertaking a rapid evidence review process, aligning evidence-based guidelines with operational realities, and iteratively revising recommendations in response to changing pandemic data. We specifically discuss the arc of evidence for corticosteroids; the noble beginnings and dangerous misinformation end of hydroxychloroquine and ivermectin; monoclonal antibodies and emerging viral variants; and patient screening and safety processes for tocilizumab, baricitinib, and nirmatrelvir-ritonavir.

The Context of "Confidence": Analyzing the Term Confidence in Resident Evaluations.

BACKGROUND: Despite similar performance metrics, women medical trainees routinely self-assess their own skills lower than men. The phenomenon of a "confidence gap" between genders, where women report lower self-confidence independent of actual ability or competency, may have an important interaction with gender differences in assessment. Identifying whether there are gender-based differences in how confidence is mentioned in written evaluations is a necessary step to understand the interaction between evaluation and the gender-based confidence gap. OBJECTIVE: To analyze faculty evaluations of internal medicine (IM) residents for gender-based patterns in the use of iterations of "confidence." DESIGN: We performed a retrospective cohort study of all inpatient faculty evaluations of University of Pennsylvania IM residents from 2018 to 2021. We performed n-gram text-mining to identify evaluations containing the terms "confident," "confidence," or "confidently." We performed univariable and multivariable logistic regression to determine the association between resident gender and references to confidence (including comments reflecting too little confidence), adjusting for faculty gender, post-graduate year (PGY), numeric rating, and service. SUBJECTS: University of Pennsylvania IM residents from 2018 to 2021. KEY RESULTS: There were 5416 evaluations of IM residents (165 women [51%], 156 men [49%]) submitted by 356 faculty members (149 women [51%]), of which 7.1 % (n=356) contained references to confidence. There was a significant positive association between the mention of confidence and women resident gender (OR 1.54, CI 1.23-1.92; p<0.001), which persisted after adjustment for faculty gender, numeric rating, and PGY level. Eighty evaluations of the cohort explicitly mentioned the resident having "too little confidence," which was also associated with women resident gender (OR 1.66, CI 1.05-2.62; p=0.031). CONCLUSION: Narrative evaluations of women residents were more likely to contain references to confidence, after adjustment for numerical score, PGY level, and faculty gender, which may perpetuate the gender-based confidence gap, introduce bias, and ultimately impact professional identity development.

Preferred treatment and prevention strategies for recurrent community-associated methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: a survey of adult and pediatric providers.

Among pediatric and adult providers, 70% preferred trimethoprim-sulfamethoxazole for directed treatment of community-associated methicillin-resistant Staphylococcus aureus skin and soft-tissue infections, although a higher proportion of pediatric compared with adult providers favored clindamycin (36% vs 8%, respectively, P < .0001). For recurrent infections, 88% of providers employed at least 1 topical decolonization strategy.

A report of human herpesvirus 6-associated encephalitis in a solid organ transplant recipient and a review of previously published cases.

Human herpesvirus 6 (HHV-6) is a common pathogen among children, classically presenting as fever and rash that resolve without specific therapy (exanthem subitum or roseola infantum). Also identified as a pathogen in hematopoietic cell transplant and solid organ transplant (SOT) recipients, it has been recognized as a cause of limbic encephalitis, characterized by confusion and amnesia, with magnetic resonance imaging findings of T2 hyperintensity of the amygdala and hippocampus. We report a case of limbic encephalitis associated with HHV-6 infection in a liver transplant recipient, and we review previously reported cases of HHV-6 encephalitis in SOT recipients.

Increased incidence of cytomegalovirus infection in high-risk liver transplant recipients receiving valganciclovir prophylaxis versus ganciclovir prophylaxis.

Optimal measures for the prevention of cytomegalovirus (CMV) in high-risk orthotopic liver transplant (OLT) patients are unknown. The charts of high-risk OLT recipients with 12 months of follow-up who were transplanted over a 44-month period were reviewed. The incidence of CMV disease in CMV-seropositive donor/CMV-seronegative recipient patients receiving valganciclovir or ganciclovir prophylaxis was compared. Sixty-six patients met the inclusion criteria and were treated with 1 of 3 prophylactic regimens: valganciclovir (900 mg daily; 27 patients), oral ganciclovir (1000 mg every 8 hours; 17 patients), or intravenous ganciclovir (6 mg/kg daily; 22 patients). Eight CMV cases occurred, all after completion of the prophylaxis. The combined incidence of CMV disease with intravenous and oral ganciclovir was lower than the incidence in valganciclovir recipients (P = 0.056; relative risk, 4.33; 95% confidence interval, 0.94-19.87). CMV disease occurred in 22.2% of valganciclovir recipients, 4.5% of intravenous ganciclovir recipients, and 5.9% of oral ganciclovir recipients. In conclusion, late-onset CMV disease occurred more frequently among high-risk liver transplant recipients treated with valganciclovir prophylaxis. The 4-fold higher incidence of CMV disease in our study supports the avoidance of valganciclovir for prophylaxis in high-risk OLT patients. Liver Transpl 15:963-967, 2009. (c) 2009 AASLD.

Effect of communication errors during calls to an antimicrobial stewardship program.

OBJECTIVE: To determine how inaccurate communication of patient data by clinicians in telephone calls to the prior-approval antimicrobial stewardship program (ASP) staff affects the incidence of inappropriate antimicrobial recommendations made by ASP practitioners. DESIGN: A retrospective cohort design was used. The accuracy of the patient data communicated was evaluated against patients' medical records to identify predetermined, clinically significant inaccuracies. Inappropriate antimicrobial recommendations were defined having been made if an expert panel unanimously rated the actual recommendations as inappropriate after reviewing vignettes derived from inpatients' medical records. SETTING: The setting was an academic medical center with a prior-approval ASP. PATIENTS: All inpatient subjects of ASP prior-approval calls were eligible for inclusion. RESULTS: Of 200 ASP telephone calls, the panel agreed about whether or not antimicrobial recommendations were inappropriate for 163 calls (82%); these 163 calls were then used as the basis for further analyses. After controlling for confounders, inaccurate communication was found to be associated with inappropriate antimicrobial recommendations (odds ratio [OR], of 2.2; P=.03). In secondary analyses of specific data types, only inaccuracies in microbiological data were associated with the study outcome (OR, 7.5; P=.002). The most common reason panelists gave for rating a recommendation as inappropriate was that antimicrobial therapy was not indicated. CONCLUSIONS: Inaccurate communication of patient data, particularly microbiological data, during prior-approval calls is associated with an increased risk of inappropriate antimicrobial recommendations from the ASP. Clinicians and ASP practitioners should work to confirm that critical data has been communicated accurately prior to use of that data in prescribing decisions.

Viral respiratory tract infections in transplant patients: epidemiology, recognition and management.

Viral respiratory tract infections (RTIs) are common causes of mild illness in immunocompetent children and adults, with occasional significant morbidity or mortality in the very young, very old or infirm. However, recipients of solid organ transplants (SOT) or haematopoietic stem cell transplants (HSCT) are at markedly increased risk for significant morbidity or mortality from these infections. The infections are generally acquired by transmission of large respiratory droplets and can be nosocomial in origin with many documented outbreaks on specialised transplant units. Typically, the infections begin as upper RTIs, with cough or rhinorrhoea predominating. Many will resolve at this stage, but more immunocompromised patients, typically closer in time to their SOT or HSCT, may develop progressive infection to lower RTI or pneumonia. The most common RTI pathogens are influenza viruses, parainfluenza viruses and respiratory syncytial viruses. Newer polymerase chain reaction-based diagnostic strategies are more sensitive than previous assays, and allow rapid and accurate diagnoses of these infections. These newer assays may also detect emerging pathogens of significance, one of which is human metapneumovirus. While diagnostic techniques have advanced significantly in the past decade, well established and effective specific treatments for these infections remain elusive. The epidemiology, clinical presentation, diagnosis and treatment of the common viral RTIs in SOT or HSCT recipients are reviewed, and recommendations presented based on a thorough review of recent literature.

Viral pneumonias other than cytomegalovirus in transplant recipients.

Community-acquired respiratory viruses (CARVs) are frequent causes of upper and lower respiratory tract infections in transplant recipients. In most series, respiratory syncytial virus and parainfluenza are the most common CARVs, followed by influenza and adenovirus. Significant morbidity and mortality are associated with these infections, particularly when they progress to pneumonia or when they are associated with bacterial or fungal coinfections. Outcomes are also poor with adenovirus, frequently reflecting disseminated infection. Efforts to prevent morbidity and mortality from CARV infection should focus on prevention, because treatment options are limited with inconclusive data to support their efficacy.

Complications related to dapsone use for Pneumocystis jirovecii pneumonia prophylaxis in solid organ transplant recipients.

Dapsone, used for prevention of Pneumocystis jirovecii infections, has been reported to cause hemolytic anemia and methemoglobinemia; its tolerability in solid organ transplant recipients is not well described. We investigated dapsone-related adverse events in patients undergoing solid organ transplantation from 1999 to 2004. Transplant providers identified patients for the investigators who then reviewed the patients' hospital and outpatient records. Sixteen solid organ transplant recipients fit case definitions for dapsone-related hemolytic anemia (n = 11) or methemoglobinemia (n = 5). Median time from event to dapsone discontinuation was 15 days; all patients improved after drug discontinuation. G6PD enzyme activity was normal in all patients whose test results were available. Dapsone may be associated with hemolytic anemia or methemoglobinemia, even with normal G6PD levels. These events are often not promptly recognized, and drug discontinuation is delayed. Dapsone-related hemolytic anemia or methemoglobinemia should be considered in solid organ transplant recipients with unexplained anemia or hypoxia.

Coadministration of oral levofloxacin with agents that impair its absorption: potential impact on emergence of resistance.

Coadministration of fluoroquinolones (FQs) with divalent or trivalent cation-containing compounds (DTCCs) inhibits FQ absorption. In a case-control study of 46 inpatients receiving oral levofloxacin and DTCCs, patients with a levofloxacin-resistant isolate had been previously exposed to nearly twice as many days of levofloxacin/DTCC coadministration (P = 0.04). There remained a borderline significant independent association between the number of days of coadministration and levofloxacin-resistant culture [adjusted odds ratio (95% confidence interval) = 1.26 (0.98, 1.63); P = 0.07], even after controlling for the length of the levofloxacin course and the duration of hospitalisation prior to initiation of levofloxacin. Efforts should be directed at modifying hospital policies for dosing of levofloxacin and DTCCs to prevent coadministration.

Successful treatment of Aspergillus prosthetic valve endocarditis with oral voriconazole.

Aspergillus endocarditis is very difficult to cure, even with aggressive surgical debridement and antifungal therapy. Patients with embolic involvement of the central nervous system have an extremely poor prognosis. We describe a patient with prosthetic valve endocarditis due to Aspergillus fumigatus who developed emboli in the brain, eye, and lower extremities. With aggressive surgical debridement of involved sites, aortic valve and root replacement, and long-term therapy with oral voriconazole, he remains without any evidence of infection 2 years later.

High rate of coadministration of di- or tri-valent cation-containing compounds with oral fluoroquinolones: risk factors and potential implications.

BACKGROUND: The characteristics of fluoroquinolone use that increase the risk of selecting for fluoroquinolone resistance remain unclear. Exposure to subtherapeutic levels of fluoroquinolone promotes bacterial development of fluoroquinolone resistance. Oral fluoroquinolone absorption is significantly impaired by coadministration with many common di- or tri-valent cation-containing compounds (DTCCs), and this interaction has been associated with therapeutic failure. However, the prevalence of, and risk factors for, in-hospital coadministration of oral fluoroquinolones with DTCCs is unknown. DESIGN: Case-control study. SETTING: A 625-bed, tertiary-care medical center. PATIENTS: All inpatients who were dispensed oral levofloxacin from July 1, 1999, to June 30, 2001, were included. Coadministration was defined by documented administration of any DTCC within 2 hours of levofloxacin. Complete coadministration was defined as coadministration complicating every dose of a course of levofloxacin. RESULTS: A subset of 3,227 (41.0%) of 7,871 doses of levofloxacin that occurred during the same calendar day as any DTCC was selected for further review. Overall, 1,904 (77.1%) of 2,470 doses of oral levofloxacin reviewed were complicated by coadministration with at least one DTCC. On multivariable analysis, an increased number of prescribed medications was significantly associated with complete coadministration (per increase of one medication: OR, 1.05; CI95, 1.01-1.10; P = .036), whereas patient location in an ICU was protective (OR, 0.51; CI95, 0.30-0.87; P = .013). If our prevalence results are extrapolated to all patients receiving oral levofloxacin at our hospital, approximately one in three doses was complicated by coadministration. CONCLUSION: Coadministration of fluoroquinolones with DTCCs is extremely common and significantly associated with polypharmacy.

Epidemiologic studies of adverse effects of anti-retroviral drugs: how well is statistical power reported.

PURPOSE: To determine whether there is a difference in average statistical power between pharmacoepidemiologic studies of anti-retroviral adverse drug effects (ADEs) sponsored by for-profit versus non-profit organizations. METHODS: We studied all published pharmacoepidemiologic studies of ADEs associated with the 15 anti-retroviral drugs approved through the end of 1999. A priori, the primary outcome was the power of each study to detect a clinically important difference in the risk for an adverse effect among patients exposed to the study drug(s). We could not evaluate this outcome because of the infrequent reporting of power calculations. We instead report the distribution of studies across a 5-tiered measure of adequacy of reporting of statistical power, as well as the sponsorship of these studies. RESULTS: Of 48 studies meeting our inclusion criteria, only 1 (2%) reported either a completed, a priori power calculation or sufficient details for readers to calculate the power to detect a pre-defined, clinically important effect. Thirty-five studies (73%) reported the minimum information required for sophisticated readers to determine the power to detect an event rate of interest to them; 6 additional studies (13%) reported confidence intervals around at least one summary effect measure and 6 (13%) provided no indication of power or uncertainty. Of the 41 studies for which sponsorship was determined, only 3 (7%) were sponsored by for-profit organizations. CONCLUSIONS: The poor reporting of statistical power in this sample suggests a need for guidelines to improve the reporting of pharmacoepidemiologic studies of ADEs. Future research is needed to determine whether the observed paucity of industry-sponsored observational studies of anti-retroviral ADEs extends to other clinical areas, and if so, to identify the causes of this phenomenon.