Serious Adverse Events and Laboratory Monitoring Regimens for Outpatient Parenteral Antimicrobial Therapy With Cefazolin and Ceftriaxone.

The optimal laboratory monitoring frequency for outpatient parenteral antimicrobial therapy-related adverse events (OPAT-AEs) during cefazolin and ceftriaxone therapy is not well defined. We identified 2.7 OPAT-AEs per 1000 sets of weekly laboratory tests in this population, suggesting that less intensive laboratory monitoring may be safe and reasonable.

Rise of the (possible) resistance: a review of susceptibility patterns for nontyphoidal Salmonella enterica in Nebraska.

Our institution sought to evaluate our antimicrobial stewardship empiric treatment recommendations for Salmonella. Results from 36 isolates demonstrated reduced susceptibilities to fluoroquinolones with 1 isolate susceptible only to ceftriaxone. Analysis supports the current recommendation of empiric ceftriaxone therapy for severe infection and updated recommendation for sulfamethoxazole-trimethoprim in non-severe infections.

Use of a beta-lactam graded challenge process for inpatients with self-reported penicillin allergies at an academic medical center.

Background: The Antimicrobial Stewardship Program (ASP) at Nebraska Medicine collaborated with a board-certified allergist to develop a penicillin allergy guidance document for treating inpatients with self-reported allergy. This guidance contains an algorithm for evaluating and safely challenging penicillin-allergic patients with beta-lactams without inpatient allergy consults being available. Methods: Following multi-disciplinary review, an order set for beta-lactam graded challenges (GC) was implemented in 2018. This contains recommended monitoring and detailed medication orders to challenge patients with various beta-lactam agents. Inpatient orders for GC from 3/2018-6/2022 were retrospectively reviewed to evaluate ordering characteristics, outcomes of the challenge, and whether documentation of the allergy history was updated. All beta-lactam challenges administered to inpatients were included, and descriptive statistics were performed. Results: Overall, 157 GC were administered; 13 with oral amoxicillin and 144 with intravenous (IV) beta-lactams. Ceftriaxone accounted for the most challenges (43%). All oral challenges were recommended by an Infectious Diseases consult service, as were a majority of IV challenges (60%). Less than one in five were administered in an ICU (19%). Almost all (n = 150, 96%) were tolerated without any adverse event. There was one reaction (1%) of hives and six (4%) involving a rash, none of which had persistent effects. Allergy information was updated in the electronic health record after 92% of the challenges. Conclusion: Both intravenous and oral beta-lactam graded challenges were implemented successfully in a hospital without a regular inpatient allergy consult service. They were well-tolerated, administered primarily in non-ICU settings, and were often ordered by non-specialist services. In patients with a self-reported penicillin allergy, these results demonstrate the utility and safety of a broadly adopted beta-lactam GC process.

Implementation of a Rapid Multiplex Polymerase Chain Reaction Pneumonia Panel and Subsequent Antibiotic De-escalation.

Background: Net effects of implementation of a multiplex polymerase chain reaction (PCR) pneumonia panel (PNP) on antimicrobial stewardship are thus far unknown. This retrospective study evaluated the real-world impact of the PNP on time to antibiotic de-escalation in critically ill patients treated for pneumonia at an academic medical center. Methods: This retrospective, quasi-experimental study included adult intensive care unit (ICU) patients with respiratory culture results from 1 May to 15 August 2019 (pre-PNP group) and adult ICU patients with PNP results from 1 May to 15 August 2020 (PNP group) at Nebraska Medical Center. Patients were excluded for the following reasons: any preceding positive coronavirus disease 2019 PCR test, lack of antibiotic receipt, or non-respiratory tract infection indications for antibiotics. The primary outcome was time to discontinuation of anti-methicillin-resistant Staphylococcus aureus (MRSA) therapy. Secondary outcomes included time to discontinuation of antipseudomonal therapy, frequency of early discontinuation for atypical coverage, and overall duration (in days) of antibiotic therapy for pneumonia. Results: Sixty-six patients in the pre-PNP group and 58 in the PNP group were included. There were significant differences in patient characteristics between groups. The median time to anti-MRSA agent discontinuation was 49.1 hours in the pre-PNP and 41.8 hours in the PNP group (P = .28). The median time to discontinuation of antipseudomonal agents was 134.4 hours in the pre-PNP versus 98.1 hours in the PNP group (P = .47). Other outcomes were numerically but not significantly improved in our sample. Conclusions: This early look at implementation of a multiplex PNP did not demonstrate a statistically significant difference in antibiotic use but lays the groundwork to further evaluate a significant real-world impact on antibiotic de-escalation in ICU patients treated for pneumonia.

Impact of specialty on the self-reported practice of using oral antibiotic therapy for definitive treatment of bloodstream infections.

Background: No established guidelines exist regarding the role of oral antibiotic therapy (OAT) to treat bloodstream infections (BSIs), and practices may vary depending on clinician specialty and experience. Objective: To assess practice patterns regarding oral antibiotic use for treatment of bacteremia in infectious diseases clinicians (IDCs, including physicians and pharmacists and trainees in these groups) and non-infectious diseases clinicians (NIDCs). Design: Open-access survey. Participants: Clinicians caring for hospitalized patients receiving antibiotics. Methods: An open-access, web-based survey was distributed to clinicians at a Midwestern academic medical center using e-mail and to clinicians outside the medical center using social media. Respondents answered questions regarding confidence prescribing OAT for BSI in different scenarios. We used χ2 analysis for categorical data evaluated association between responses and demographic groups. Results: Of 282 survey responses, 82.6% of respondents were physicians, 17.4% pharmacists, and IDCs represented 69.2% of all respondents. IDCs were more likely to select routine use of OAT for BSI due to gram-negative anaerobes (84.6% vs 59.8%; P < .0001), Klebsiella spp (84.5% vs 69.0%; P < .009), Proteus spp (83.6% vs 71.3%; P < .027), and other Enterobacterales (79.5% vs 60.9%; P < .004). Our survey results revealed significant differences in selected treatment of Staphylococcus aureus syndromes. Fewer IDCs than NIDCs selected OAT to complete treatment for methicillin-resistant S. aureus (MRSA) BSI due to gluteal abscess (11.9% vs 25.6%; P = .012) and methicillin-susceptible S. aureus (MSSA) BSI due to septic arthritis (13.9% vs 20.9%; P = .219). Conclusions: Practice variation and discordance with evidence for the use of OAT for BSIs exists among IDCs versus NIDCs, highlighting opportunities for education in both clinician groups.

ADAR Mediated RNA Editing Modulates MicroRNA Targeting in Human Breast Cancer.

RNA editing by RNA specific adenosine deaminase acting on RNA (ADAR) is increasingly being found to alter microRNA (miRNA) regulation. Editing of miRNA transcripts can affect their processing, as well as which messenger RNAs (mRNAs) they target. Further, editing of target mRNAs can also affect their complementarity to miRNAs. Notably, ADAR editing is often increased in malignancy with the effect of these RNA changes being largely unclear. In addition, numerous reports have now identified an array of miRNAs that directly contribute to various malignancies although the majority of their targets remain largely undefined. Here we propose that modulating the targets of miRNAs via mRNA editing is a frequent occurrence in cancer and an underappreciated participant in pathology. In order to more accurately characterize the relationship between these two regulatory processes, this study examined RNA editing events within mRNA sequences of two breast cancer cell lines (MCF-7 and MDA-MB-231) and determined whether or not these edits could modulate miRNA associations. Computational analyses of RNA-Seq data from these two cell lines identified over 50,000 recurrent editing sites within human mRNAs, and many of these were located in 3' untranslated regions (UTRs). When these locations were screened against the list of currently-annotated miRNAs we discovered that editing caused a subset (~9%) to have significant alterations to mRNA complementarity. One miRNA in particular, miR-140-3p, is known to be misexpressed in many breast cancers, and we found that mRNA editing allowed this miRNA to directly target the apoptosis inducing gene DFFA in MCF-7, but not in MDA-MB-231 cells. As these two cell lines are known to have distinct characteristics in terms of morphology, invasiveness and physiological responses, we hypothesized that the differential RNA editing of DFFA in these two cell lines could contribute to their phenotypic differences. Indeed, we confirmed through western blotting that inhibiting miR-140-3p increases expression of the DFFA protein product in MCF-7, but not MDA-MB-231, and further that inhibition of miR-140-3p also increases cellular growth in MCF-7, but not MDA-MB-231. Broadly, these results suggest that the creation of miRNA targets may be an underappreciated function of ADAR and may help further elucidate the role of RNA editing in tumor pathogenicity.

Human snoRNA-93 is processed into a microRNA-like RNA that promotes breast cancer cell invasion.

Genetic searches for tumor suppressors have recently linked small nucleolar RNA misregulations with tumorigenesis. In addition to their classically defined functions, several small nucleolar RNAs are now known to be processed into short microRNA-like fragments called small nucleolar RNA-derived RNAs. To determine if any small nucleolar RNA-derived RNAs contribute to breast malignancy, we recently performed a RNA-seq-based comparison of the small nucleolar RNA-derived RNAs of two breast cancer cell lines (MCF-7 and MDA-MB-231) and identified small nucleolar RNA-derived RNAs derived from 13 small nucleolar RNAs overexpressed in MDA-MB-231s. Importantly, we find that inhibiting the most differentially expressed of these small nucleolar RNA-derived RNAs (sdRNA-93) in MDA-MB-231 cells results primarily in a loss of invasiveness, whereas increased sdRNA-93 expression in either cell line conversely results in strikingly enhanced invasion. Excitingly, we recently determined sdRNA-93 expressions in small RNA-seq data corresponding to 116 patient tumors and normal breast controls, and while we find little sdRNA-93 expression in any of the controls and only sporadic expression in most subtypes, we find robust expression of sdRNA-93 in 92.8% of Luminal B Her2+tumors. Of note, our analyses also indicate that at least one of sdRNA-93's endogenous roles is to regulate the expression of Pipox, a sarcosine metabolism-related protein whose expression significantly correlates with distinct molecular subtypes of breast cancer. We find sdRNA-93 can regulate the Pipox 3'UTR via standard reporter assays and that manipulating endogenous sdRNA-93 levels inversely correlates with altered Pipox expression. In summary, our results strongly indicate that sdRNA-93 expression actively contributes to the malignant phenotype of breast cancer through participating in microRNA-like regulation.

Sensitivity of metal nanoparticle surface plasmon resonance to the dielectric environment.

Electrodynamic simulations of gold nanoparticle spectra were used to investigate the sensitivity of localized surface plasmon band position to the refractive index, n, of the medium for nanoparticles of various shapes and nanoshells of various structures. Among single-component nanoparticles less than 130 nm in size, sensitivities of dipole resonance positions to bulk refractive index are found to depend only upon the wavelength of the resonance and the dielectric properties of the metal and the medium. Among particle plasmons that peak in the frequency range where the real part of the metal dielectric function varies linearly with wavelength and the imaginary part is small and slowly varying, the sensitivity of the peak wavelength, lambda, to refractive index, n, is found to be a linearly increasing function of lambda, regardless of the structural features of the particle that determine lambda. Quasistatic theory is used to derive an analytical expression for the refractive index sensitivity of small particle plasmon peaks. Through this analysis, the dependence of sensitivity on band position is found to be determined by the wavelength dependence of the real part, epsilon', of the particle dielectric function, and the sensitivity results are found to extend to all particles with resonance conditions of the form, epsilon' = -2chin(2), where chi is a function of geometric parameters and other constants. The sensitivity results observed using accurate computational methods for dipolar plasmon bands of gold nanodisks, nanorods, and hollow nanoshells extend, therefore, to particles of other shapes (such as hexagonal and chopped tetrahedral), composed of other metals, and to higher-order modes. The bulk refractive index sensitivity yielded by the theory serves as an upper bound to sensitivities of nanoparticles on dielectric substrates and sensitivities of nanoparticles to local refractive index changes, such as those associated with biomolecule sensing.