Long-Acting Cabotegravir/Rilpivirine Concentrations in Combination With Intravenous Rifampin: A Case Report.

As antiretroviral therapy advancements focus on long-acting medications, there is a need to assess the potential impact of drug-drug interactions. We present a real-world case of long-acting cabotegravir/rilpivirine co-administered with intravenous rifampin. The combination resulted in both cabotegravir and rilpivirine concentrations falling below 4 times the protein-adjusted IC90.

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.

Targeted Immuno-Antiretroviral to Promote Dual Protection against HIV: A Proof-of-Concept Study.

The C-C motif chemokine receptor-5 (CCR5) expression on the T-cell surface is the prime barrier to HIV/AIDS eradication, as it promotes both active human immunodeficiency virus (HIV)-infection and latency; however, antiretrovirals (ARVs) suppress plasma viral loads to non-detectable levels. Keeping this in mind, we strategically designed a targeted ARVs-loaded nanoformulation that targets CCR5 expressing T-cells (e.g., CD4+ cells). Conceptually, CCR5-blocking and targeted ARV delivery would be a dual protection strategy to prevent HIV infection. For targeting CCR5+ T-cells, the nanoformulation was surface conjugated with anti-CCR5 monoclonal antibodies (CCR5 mAb) and loaded with dolutegravir+tenofovir alafenamide (D+T) ARVs to block HIV replication. The result demonstrated that the targeted-ARV nanoparticle's multimeric CCR5 binding property improved its antigen-binding affinity, prolonged receptor binding, and ARV intracellular retention. Further, nanoformulation demonstrated high binding affinity to CCR5 expressing CD4+ cells, monocytes, and other CCR5+ T-cells. Finally, the short-term pre-exposure prophylaxis study demonstrated that prolonged CCR5 blockage and ARV presence further induced a "protective immune phenotype" with a boosted T-helper (Th), temporary memory (TM), and effector (E) sub-population. The proof-of-concept study that the targeted-ARV nanoformulation dual-action mechanism could provide a multifactorial solution toward achieving HIV "functional cure."

Turmeric-Associated Drug-Induced Liver Injury.

Turmeric is a common herbal supplement used for its possible anti-inflammatory and other properties. It is marketed as safe with few reports of major adverse effects directly related to oral supplementation. We report a case of turmeric supplement-induced liver injury in a 49-year-old woman admitted with elevated aspartate aminotransferase and alanine aminotransferase with no history of liver disease or alcohol use disorder. Thus, this case re-emphasizes the importance of evaluating herbal and dietary supplements as potential drug-induced liver injury causes.

A Concept Evaluation Study of a New Combination Bictegravir plus Tenofovir Alafenamide Nanoformulation with Prolonged Sustained-Drug-Release Potency for HIV-1 Preexposure Prophylaxis.

The antiretroviral treatment (ART) approach is the best-prescribed approach to date for preexposure prophylaxis (PrEP) for high-risk individuals. However, the daily combination antiretroviral (cARV) regimen has become cumbersome for healthy individuals, leading to nonadherence. Recent surveys showed high acceptance of parenteral sustained-release ART enhancing PrEP adherence. Our approach is to design a parenteral nanoparticle (NP)-based cARV sustained-release (cARV-SR) system as long-acting HIV PrEP. Here, we report a new combination of two potent ARVs (tenofovir alafenamide fumarate [TAF] and bictegravir [BIC]) loaded as a nanoformulation intended as a cARV-SR for PrEP. The BIC+TAF NPs were fabricated by using a standardized in-house methodology. In vitro intracellular kinetics, cytotoxicity, and HIV-1 protection studies demonstrated that BIC+TAF encapsulation prolonged drug retention, reduced drug-associated cytotoxicity, and enhanced HIV protection. In human peripheral blood mononuclear cells, nanoformulated BIC+TAF demonstrated significant (P < 0.05) improvement in the drug's selectivity index by 472 times compared to the BIC+TAF in solution. In vivo pharmacokinetic study of BIC, TAF, and respective drug metabolites in female BALB/c mice after single subcutaneous doses of BIC+TAF NPs demonstrated plasma drug concentrations of BIC and tenofovir above the intracellular 50% inhibitory concentration during the entire 30-day study period and prolonged persistence of both active drugs in the HIV target organs, including the vagina, colon, spleen, and lymph nodes. This report demonstrates that the encapsulation of BIC+TAF in a nanoformulation improved its therapeutic selectivity and the in vivo pharmacokinetics of free drugs. Based on these preliminary studies, we hypothesize that cARV-SR has potential as an innovative once-monthly delivery treatment for PrEP.