Supplementation of standard growth media (cation-adjusted Mueller-Hinton Broth [CAMHB]) with bicarbonate (NaHCO3) increases β-lactam susceptibility of selected methicillin-resistant Staphylococcus aureus (MRSA) strains (“NaHCO3 responsive”). This “sensitization” phenomenon translated to enhanced β-lactam efficacy in a rabbit model of endocarditis. The present study evaluated NaHCO3-mediated β-lactam MRSA sensitization using an ex vivo pharmacodynamic model, featuring simulated endocardial vegetations (SEVs), to more closely mimic the host microenvironment. Four previously described MRSA strains were used: two each exhibiting in vitro NaHCO3-responsive or NaHCO3-nonresponsive phenotypes. Cefazolin (CFZ) and oxacillin (OXA) were evaluated in CAMHB with or without NaHCO3. Intra-SEV MRSA killing was determined over 72-h exposures. In both “responsive” strains, supplementation with 25 mM or 44 mM NaHCO3 significantly reduced β-lactam MICs to below the OXA susceptibility breakpoint (≤4 mg/liter) and resulted in bactericidal activity (≥3-log killing) in the model for both OXA and CFZ. In contrast, neither in vitro-defined nonresponsive MRSA strain showed significant sensitization in the SEV model to either β-lactam. At both NaHCO3 concentrations, the fractional time above MIC was >50% for both CFZ and OXA in the responsive MRSA strains. Also, in media containing RPMI plus 10% Luria-Bertani broth (proposed as a more host-mimicking microenvironment and containing 25 mM NaHCO3), both CFZ and OXA exhibited enhanced bactericidal activity against NaHCO3-responsive strains in the SEV model. Neither CFZ nor OXA exposures selected for emergence of high-level β-lactam-resistant mutants within SEVs. Thus, in this ex vivo model of endocarditis, in the presence of NaHCO3 supplementation, both CFZ and OXA are highly active against MRSA strains that demonstrate similar enhanced susceptibility in NaHCO3-supplemented media in vitro.
Background: Fixed-dose (FD) regimens of 4-factor prothrombin complex concentrate (4F-PCC) may be effective for the emergent reversal of warfarin; however, the optimal dosing is unknown. Our institution transitioned to a FD regimen of 1000 or 2000 units of 4F-PCC based on indication. Objective: The purpose of this study is to report our experience with FD 4F-PCC compared with a historical weight-based dosing cohort for warfarin reversal. Methods: A retrospective analysis was conducted for 3 groups: central nervous system (CNS) bleeds regardless of international normalized ratio (INR), non-CNS bleeds with an initial INR ≤6, and non-CNS bleeds with an initial INR ≥6.1. The primary outcome of the study was achievement of the target INR. Results: There were 54 patients with a CNS bleed, 153 with a non-CNS bleed and INR ≤6, and 19 with a non-CNS bleed and INR ≥6.1. In the CNS bleeding group, weight-based and FD achieved target INR 79.4% and 70% ( P = 0.52). In the INR ≥6.1 non-CNS bleeding group, weight-based and FD achieved target INR 100% and 70% ( P = 0.21). In the INR ≤6 non-CNS bleeding group, weight-based and FD achieved target INR 86.4% and 57.5% ( P = 0.0002). Conclusion and Relevance: An FD strategy of 2000 units for warfarin reversal for CNS bleeds or INR ≥6.1 was comparable to weight-based dosing. The FD strategy of 1000 units for INR ≤6 achieved target INR less often than weight-based dosing. Application of findings suggest that higher doses may be needed to achieve target INR.
Word Count: 3963 25 2 ABSTRACT 26 Supplementation of standard growth media (cation-adjusted Mueller-Hinton Broth 27[CAMHB]) with bicarbonate (NaHCO 3 ) significantly increases β-lactam susceptibility of selected 28 MRSA strains ("NaHCO 3 -responsive"). This "sensitization" phenomenon translated to enhanced 29 β-lactam efficacy in a rabbit model of endocarditis. The present study evaluated NaHCO 3 -30 mediated β-lactam MRSA sensitization using an ex vivo pharmacodynamic model, featuring 31 simulated endocardial vegetations (SEVs), to more closely mimic the host microenvironment. 32Four previously described MRSA strains were used: two each exhibiting in vitro "NaHCO 3 -33 responsive" or "NaHCO 3 -nonresponsive" phenotypes. Cefazolin (CFZ) and oxacillin (OXA) were 34 evaluated in CAMHB±NaHCO 3 . Intra-SEV MRSA killing was determined over 72 hr exposure. In 35 both NaHCO 3 -responsive strains, supplementation with 25 mM or 44 mM NaHCO 3 significantly 36 reduced β-lactam MICs to below the OXA susceptibility breakpoint (≤ 4 mg/L) resulting in 37 bactericidal activity (≥ 3 log kill) in the model for both OXA and CFZ. In contrast, neither in vitro-38 defined NaHCO 3 -nonresponsive MRSA strains showed significant sensitization in the SEV 39 model to either β-lactam. At both NaHCO 3 concentrations, the fractional time-above-MIC was 40 >50% for both CFZ and OXA in the NaHCO 3 -responsive MRSA. Also, in RPMI+10% LB media 41 (proposed as a more host-mimicking microenvironment and containing 25 mM NaHCO 3 ), both 42 CFZ and OXA exhibited enhanced bactericidal activity against each NaHCO 3 -responsive strain 43 in the SEV model. Neither CFZ nor OXA exposures selected for high-level β-lactam-resistant 44 mutants within SEVs. Thus, in this ex vivo model of endocarditis, in the presence of NaHCO 3 45 supplementation, both CFZ and OXA are highly active against MRSA strains that demonstrate 46 similar enhanced susceptibility in NaHCO 3 -supplemented media in vitro. 47 3 INTRODUCTION 48
Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Use of autoverification has decreased in many emergency departments (EDs) with the expansion of emergency medicine (EM) pharmacists. Few studies have evaluated ways to prioritize verification of medications. Here we describe a process to design, implement, and measure the safety of autoverification of low-risk, high-volume medications. Summary A 3-month retrospective review of medications ordered and administered in the ED generated a list of medications to be considered for autoverification. Concurrently, a novel risk stratification tool was created to identify low-risk medications. Taking these together, medications that were high volume and low risk were considered potentially autoverified medications (PAMs). To evaluate the safety of PAMs, a retrospective review of the ED medication orders placed before implementation of autoverification was performed. A total of 7,433 medication orders were reviewed. Of these, 3,057 orders (41%) were identified as PAMs. EM pharmacists verified 2,982 (97.5%) of the orders without changes. Of the remaining 93 orders that were modified or discontinued and met autoverification criteria, only 2 (0.07%) were identified as potentially inappropriate for autoverification. Conclusion Low-risk, high-volume medications can be safely autoverified in the ED by using a systematic approach to order selection. Using these methods can provide large decreases in verification volume, close to 41%, without compromising patient safety.
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