The Integration of Physical Therapists and Occupational Therapists into Burn Wound Care Increases Therapist Productivity, Job Satisfaction, and Multidisciplinary Collaboration.

When attempting to deliver specialized rehabilitation therapy interventions, physical therapists (PTs) and occupational therapists (OTs) must account for dynamic and logistical patient factors such as: daily wound care, pain, difficultly progressing range of motion with dressings donned, and ongoing surgical interventions. Additionally, they must attain institution-specific productivity standards. Given burn patients often require considerable multidisciplinary interventions, efficiently planning and delivering rehabilitation therapy interventions within productivity expectations may prove difficult. The purpose of this study was to assess the feasibility of integrating rehabilitation therapists, PTs and OTs, into daily burn wound care by investigating therapist productivity and multidisciplinary perceptions of this practice change. The quality improvement project involved six rehabilitation therapists (three PTs and three OTs) practicing exclusively in the burn unit within an American Burn Association (ABA) verified burn center at an urban, tertiary care academic medical center. One rehabilitation therapist was responsible for providing interventions within the burn wound care team five days a week. General duties included wound assessment, functional wound dressings, and skilled therapeutic interventions such as manual therapy, therapeutic exercise, and compression interventions. The primary outcome was changes in group productivity and individual therapist productivity, as measured by total billed CPT codes per hour worked, which were tracked 22 weeks pre- and 28 weeks post-implementation. Program feasibility and general perceptions were assessed by a qualitative questionnaire. For both the entire group of therapists and each individual rehabilitation therapist, billed CPT codes per hour increased post implementation, 1.81 versus 1.54 (p=0.005) and a matched increase of 0.27/hr (p=0.003). Of the 23 survey respondents, 96% had a favorable impression of the program and reported it eased staffing demands. All respondents reported improved unit workflow and multidisciplinary communication. The majority of multidisciplinary burn team members actively supported the pilot program and commented on improvements in patient care. Full-time rehabilitation therapy participation in wound care increases therapist productivity and job satisfaction. Future efforts, however, should focus on measuring specific patient outcomes and cost as a result of therapist integration into daily wound care practice.

Bone and Skin/Subcutaneous Tissue Concentrations of Cefiderocol During Treatment of Extensively Drug-Resistant Pseudomonas aeruginosa.

Pyoderma gangrenosum is a rare dermatologic disorder that disrupts the skin barrier, requiring immunosuppressive therapy. We successfully used cefiderocol for the treatment of an extensively drug-resistant Pseudomonas aeruginosa bacteremia, and presumed osteomyelitis in a patient with severe pyoderma gangrenosum and associated immunosuppressive therapy while being medically optimized for skin grafting. We obtained bone and skin/subcutaneous tissue while the patient was on cefiderocol under an institutional review board-approved biologic waste recovery protocol. Cefiderocol concentrations in bone and skin/subcutaneous tissue were 13.9 and 35.9 mcg/g, respectively. The patient recovered from bacteremia and underwent autografting without further complications. Cefiderocol at approved dosing of 2 g IV (3-hour infusion) every 8 hours resulted in bone and skin/subcutaneous tissue concentrations adequate to treat extensively drug-resistant Gram-negative bacteria that remain susceptible to cefiderocol.

An Appraisal of Pharmacotherapy-Pertinent Literature Published in 2021 and 2022 for Clinicians Caring for Patients With Thermal or Inhalation Injury.

Studies focusing on pharmacotherapy interventions to aid patients after thermal injury are a minor focus in burn injury-centered studies and published across a wide array of journals, which challenges those with limited resources to keep their knowledge current. This review is a renewal of previous years' work to facilitate extraction and review of the most recent pharmacotherapy-centric studies in patients with thermal and inhalation injury. Twenty-three geographically dispersed, board-certified pharmacists participated in the review. A Medical Subject Heading-based, filtered search returned 2336 manuscripts over the previous 2-year period. After manual review, 98 (4%) manuscripts were determined to have a potential impact on current pharmacotherapy practice. The top 10 scored manuscripts are discussed. Only 17% of those reviewed were assessed to likely have little effect on current practice. The overall impact of the current cohort was higher than previous editions of this review, which is encouraging. There remains a need for investment in well-designed, high-impact, pharmacotherapy-pertinent research for patients sustaining thermal or inhalation injuries.

A methodology of phenotyping ICU patients from EHR data: High-fidelity, personalized, and interpretable phenotypes estimation.

OBJECTIVE: Computing phenotypes that provide high-fidelity, time-dependent characterizations and yield personalized interpretations is challenging, especially given the complexity of physiological and healthcare systems and clinical data quality. This paper develops a methodological pipeline to estimate unmeasured physiological parameters and produce high-fidelity, personalized phenotypes anchored to physiological mechanics from electronic health record (EHR). METHODS: A methodological phenotyping pipeline is developed that computes new phenotypes defined with unmeasurable computational biomarkers quantifying specific physiological properties in real time. Working within the inverse problem framework, this pipeline is applied to the glucose-insulin system for ICU patients using data assimilation to estimate an established mathematical physiological model with stochastic optimization. This produces physiological model parameter vectors of clinically unmeasured endocrine properties, here insulin secretion, clearance, and resistance, estimated for individual patient. These physiological parameter vectors are used as inputs to unsupervised machine learning methods to produce phenotypic labels and discrete physiological phenotypes. These phenotypes are inherently interpretable because they are based on parametric physiological descriptors. To establish potential clinical utility, the computed phenotypes are evaluated with external EHR data for consistency and reliability and with clinician face validation. RESULTS: The phenotype computation was performed on a cohort of 109 ICU patients who received no or short-acting insulin therapy, rendering continuous and discrete physiological phenotypes as specific computational biomarkers of unmeasured insulin secretion, clearance, and resistance on time windows of three days. Six, six, and five discrete phenotypes were found in the first, middle, and last three-day periods of ICU stays, respectively. Computed phenotypic labels were predictive with an average accuracy of 89%. External validation of discrete phenotypes showed coherence and consistency in clinically observable differences based on laboratory measurements and ICD 9/10 codes and clinical concordance from face validity. A particularly clinically impactful parameter, insulin secretion, had a concordance accuracy of 83%±27%. CONCLUSION: The new physiological phenotypes computed with individual patient ICU data and defined by estimates of mechanistic model parameters have high physiological fidelity, are continuous, time-specific, personalized, interpretable, and predictive. This methodology is generalizable to other clinical and physiological settings and opens the door for discovering deeper physiological information to personalize medical care.

Augmented Renal Function in Burn Patients: Occurrence and Discordance With Commonly Used Methods to Assess Renal Function.

Augmented renal clearance (ARC) is defined by supraphysiologic renal function and is associated with drug failure due to subtherapeutic drug exposure. Burn patients are cited as being at high risk for ARC, yet rates of ARC have not been well described. This retrospective study described the prevalence and incidence of ARC, and compared 12-hour urine collection values (CrCl-12) vs. common estimates of renal function in assessed patients at an American Burn Association-verified burn center. All thermally injured burn patients with a CrCl-12 result were included. ARC was defined as a CrCl-12 >130 ml/min. Cockcroft-Gault, modification of diet in renal disease (MDRD), and CKD-EPI-2021 estimates were calculated. Over 13 months, 163 CrCl-12 results were collected in 68 patients at a median of 9 days from admission with an average value of 160 ml/min. The median total body surface area (total body surface area [TBSA]%) was 17.25%. ARC prevalence was 70.6% with an incidence of 66.3% in all CrCl-12 assessments. Those with ARC were less likely to have heart failure, P = .007. Age, TBSA%, and trauma were not different between those with or without ARC. ARC incidences in those with TBSAs of ≥20%, <20%, or <10%, were 70.5%, 58.6%, and 76.7%, respectively. Agreement of Cockcroft-Gault, MDRD, and CKD-EPI-2021 to CrCl-12 was moderate to weak and frequently failed to identify ARC. ARC is common in burn patients, regardless of TBSA%. Widely accepted estimations of renal function may be incorrect resulting in under-dosing of medications. Additional research is required to identify burn patients at greatest risk for ARC and subsequent dosing strategies to maintain pharmacologic efficacy without unduetoxicity.

Management of noncytotoxic extravasation injuries: A focused update on medications, treatment strategies, and peripheral administration of vasopressors and hypertonic saline.

Extravasation is the leakage of intravenous solutions into surrounding tissues, which can be influenced by drug properties, infusion techniques, and patient-related risk factors. Although peripheral administration of vesicants may increase the risk of extravasation injuries, the time and resources required for central venous catheter placement may delay administration of time-sensitive therapies. Recent literature gathered from the growing use of peripheral vasopressors and hypertonic sodium suggests low risk of harm for initiating these emergent therapies peripherally, which may prevent delays and improve patient outcomes. Physiochemical causes of tissue injury include vasoconstriction, pH-mediated, osmolar-mediated, and cytotoxic mechanisms of extravasation injuries. Acidic agents, such as promethazine, amiodarone, and vancomycin, may cause edema, sloughing, and necrosis secondary to cellular desiccation. Alternatively, basic agents, such as phenytoin and acyclovir, may be more caustic due to deeper tissue penetration of the dissociated hydroxide ions. Osmotically active agents cause cellular damage as a result of osmotic shifts across cellular membranes in addition to agent-specific toxicities, such as calcium-induced vasoconstriction and calcifications or arginine-induced leakage of potassium causing apoptosis. A new category has been proposed to identify absorption-refractory mechanisms of injury in which agents such as propofol and lipids may persist in the extravasated space and cause necrosis or compartment syndrome. Pharmacological antidotes may be useful in select extravasations but requires prompt recognition and frequently complex administration strategies. Historically, intradermal phentolamine has been the preferred agent for vasopressor extravasations, but frequent supply shortages have led to the emergence of terbutaline, a ß2 -agonist, as an acceptable alternative treatment option. For hyperosmolar and pH-related mechanisms of injuries, hyaluronidase is most commonly used to facilitate absorption and dispersion of injected agents. However, extravasation management is largely supportive and requires a protocolized multidisciplinary approach for early detection, treatment, and timely surgical referral when required to minimize adverse events.

Correlation Between and Nursing Satisfaction With CIWA-Ar, mMINDS, and SEWS Scoring Tools for the Assessment of Severe Alcohol Withdrawal Syndrome in ICU Patients.

BACKGROUND: Management of alcohol withdrawal syndrome (AWS) requires bedside assessments of symptom severity to guide therapies. Commonly used assessment tools are the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), the modified Minnesota Detoxification Scale (mMINDS) and the Severity of Ethanol Withdrawal Scale (SEWS). OBJECTIVE: To determine strength of correlation between the CIWA-Ar, mMINDS, and SEWS for bedside assessment of severe AWS and to survey nurses regarding ease of use of each tool. METHODS: A single-center prospective correlation study of the three assessment tools performed by bedside nurses on patients with AWS followed by a questionnaire assessing ease of use of each tool (1 being the easiest and 9 being the hardest). RESULTS: A total of 66 correlation assessments were performed by 49 nurses in 21 patients with AWS. Bedside CIWA-Ar, mMINDS, and SEWS were 14 ± 8.3, 13.9 ± 6.5, and 10.1 ± 4.5, respectively. The Pearson correlation coefficients were 0.814 (95% CI, 0.714-0.881) between CIWA-Ar and mMINDS; 0.722 (95% CI, 0.585-0.820) between CIWA-Ar and SEWS; and 0.658 (95% CI, 0.498-0.775) between SEWS and mMINDS. Nurse ratings for ease of use were 4 ± 2.3 for CIWA-Ar, 2.9 ± 2 for mMINDS (p=0.0044 vs. CIWA-Ar), and 4.8 ± 2.1 for SEWS (p=0.036 vs. CIWA-Ar, p<0.0001 vs. mMINDS). Forty-six (69.7%) respondents preferred mMINDS versus 14 (21.2%) and 6 (9.1%) respondents favored CIWA-Ar and SEWS, respectively. CONCLUSION: Correlations between the three scoring tools in severe AWS are robust. Only mMINDS was considered easy to use by nurses. It was the preferred tool.

Burn Injury and Augmented Renal Clearance: A Case for Optimized Piperacillin-Tazobactam Dosing.

Patients with burn injuries are at high risk for infection as well as altered antimicrobial pharmacokinetics. Patients suffering from a burn injury, generally encompassing a total body surface area (TBSA) ≥ 20%, have been cited as at risk for augmented renal clearance (ARC). Our case report describes an obese patient with 3.2% TBSA partial thickness burns who suffered from burn wound cellulitis with Pseudomonas aeruginosa. Measured CLcr documented the presence of ARC, and 22.5 grams daily continuous infusion of piperacillin-tazobactam was initiated. Therapeutic monitoring of piperacillin at steady state was 78 mcg/mL, achieving the prespecified goal piperacillin concentration of 100% 4-times the minimum inhibitory concentration assuming MIC for susceptible P. aeruginosa at 16/4 mcg/mL per Clinical Laboratory Standards Institute. Available literature suggests younger critically ill patients with lower organ failure scores, and for a burn injury, a higher percentage of TBSA, are most likely to exhibit ARC which does not entirely align with the characteristics of our patient. In addition, piperacillin-tazobactam has been associated with altered pharmacokinetics in ARC, burn, and obese populations, demonstrating failure to meet target attainment with standard doses. We suggest a continuous infusion of piperacillin-tazobactam be used when ARC is identified. This case report describes the unique findings of ARC in a non-critically ill burn patient and rationalizes the need for further prospective research to classify incidence, risk factors, and appropriate antimicrobial regimens for burn patients with ARC.

Ketamine in Critically Ill Patients: Use, Perceptions, and Potential Barriers.

Objective: To evaluate practitioner use of ketamine and identify potential barriers to use in acutely and critically ill patients. To compare characteristics, beliefs, and practices of ketamine frequent users and non-users. Methods: An online survey developed by members of the Society of Critical Care Medicine (SCCM) Clinical Pharmacy and Pharmacology Section was distributed to physician, pharmacist, nurse practitioner, physician assistant and nurse members of SCCM. The online survey queried SCCM members on self-reported practices regarding ketamine use and potential barriers in acute and critically ill patients. Results: Respondents, 341 analyzed, were mostly adult physicians, practicing in the United States at academic medical centers. Clinicians were comfortable or very comfortable using ketamine to facilitate intubation (80.0%), for analgesia (77.9%), procedural sedation (79.4%), continuous ICU sedation (65.8%), dressing changes (62.4%), or for asthma exacerbation and status epilepticus (58.8% and 40.4%). Clinicians were least comfortable with ketamine use for alcohol withdrawal and opioid detoxification (24.7% and 23.2%). Most respondents reported "never" or "infrequently" using ketamine preferentially for continuous IV analgesia (55.6%) or sedation (61%). Responses were mixed across dosing ranges and duration. The most common barriers to ketamine use were adverse effects (42.6%), other practitioners not routinely using the medication (41.5%), lack of evidence (33.5%), lack of familiarity (33.1%), and hospital/institutional policy guiding the indication for use (32.3%). Conclusion: Although most critical care practitioners report feeling comfortable using ketamine, there are many inconsistencies in practice regarding dose, duration, and reasons to avoid or limit ketamine use. Further educational tools may be targeted at practitioners to improve appropriate ketamine use.

Comparison of Sequential Dalbavancin With Standard-of-Care Treatment for Staphylococcus aureus Bloodstream Infections.

Background: Dalbavancin (DAL) is a long-acting lipoglycopeptide with activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). This study investigates DAL as sequential therapy in S. aureus bloodstream infections (BSIs). Methods: We conducted a retrospective cohort study from 2014 to 2021 comparing sequential DAL with standard-of-care therapy (SoC) for S. aureus BSI. The primary outcome was 90-day clinical failure (90-day all-cause mortality or 90-day recurrence). Secondary outcomes were incidence of acute kidney injury, creatinine phosphokinase elevations, catheter-related thrombosis, and hospital-acquired infections. Analyses were adjusted using inverse probability of treatment weighting (IPTW). Results: Overall, 225 patients (45 DAL, 180 SoC) were included. DAL patients had a higher incidence of community-acquired infection and persons who use drugs; SoC patients had more comorbidities and a longer duration of bacteremia. MRSA incidence was similar between the DAL and SoC groups. The median length of stay was 16 days among DAL recipients compared with 24 days among SoC recipients. Central catheter placement was 17.8% compared with 57.2% in the SoC group. Ninety-day clinical failure occurred in 13.3% and 18.3% of participants in the DAL and SOC groups, respectively. In IPTW-adjusted analysis, sequential DAL was not associated with 90-day clinical failure (adjusted odds ratio, 0.94; 95% CI, 0.333-2.32). Conclusions: This study provides preliminary evidence that select patients with S. aureus BSI treated with sequential DAL have similar clinical failure rates, with significant reductions in catheter placement and hospital length of stay compared with SoC. Further prospective evaluation is needed.

Evaluation of safety and efficacy outcomes of direct oral anticoagulants versus warfarin in normal and extreme body weights for the treatment of atrial fibrillation or venous thromboembolism.

Despite evolving evidence, the use of direct oral anticoagulants (DOACs) in patients with extremes of body weight remains controversial. This study aimed to measure the impact of DOACs compared to warfarin on safety and efficacy outcomes in extreme body weight patients. This multi-center, health system, retrospective study examined the outcomes of patients with all body weights and extreme body weights prescribed a DOAC (rivaroxaban, apixaban, dabigatran, edoxaban) or warfarin for atrial fibrillation or venous thromboembolism over a 9-year period. The primary outcome was a composite of thromboembolism, symptomatic recurrent VTE, or severe bleeding; analyzed by pre-determined BMI cutoffs. A total of 19,697 patients were included in the study: 11,604 in the DOAC group and in the 8093 in the warfarin group. 295 patients were underweight and 9108 patients were pre-obese to obese class 3. After adjusting for potential confounders, warfarin patients had higher odds of experiencing the composite outcome compared to DOAC patients (OR 1.337, 95% CI 1.212-1.475). Additionally, obese patients were 24.6% more likely to experience the outcome compared to normal BMI patients. Adjusted modeling showed that warfarin patients experienced higher bleed rates compared to DOAC patients (OR 1.432, 95% CI 1.266-1.620). Obese patients were less likely to be diagnosed with a bleed (OR 0.749, 95% CI 0.658-0.854), and underweight patients were more likely to be diagnosed with a bleed (OR 1.522, 95% CI 1.095-2.115) compared to normal BMI patients. In conclusion, DOACs for atrial fibrillation or VTE in patients with extreme body weights appear safe and effective when compared to warfarin.

Real-World Use of Tedizolid Phosphate for 28 Days or More: A Case Series Describing Tolerability and Clinical Success.

Tedizolid has activity against Gram-positive pathogens as well as Mycobacterium spp and Nocardia spp. Real-world evidence supporting long-term tolerability and clinical success of tedizolid is lacking. Prolonged tedizolid therapy (median, 188 days; interquartile range, 62-493 days) appeared to be well tolerated in 37 patients (8.1% experienced adverse effect leading to discontinuation). Clinical success was 81.3% in those evaluated.

Correlation of antimicrobial fraction unbound and sieving coefficient in critically ill patients on continuous renal replacement therapy: a systematic review.

BACKGROUND: Fraction unbound has been used as a surrogate for antimicrobial sieving coefficient (SC) to predict extracorporeal clearance in critically ill patients on continuous renal replacement therapy (CRRT), but this is based largely on expert opinion. OBJECTIVES: To examine relationships between package insert-derived fraction unbound (Fu-P), study-specific fraction unbound (Fu-S), and SC in critically ill patients receiving CRRT. METHODS: English-language studies containing patient-specific in vivo pharmacokinetic parameters for antimicrobials in critically ill patients requiring CRRT were included. The primary outcome included correlations between Fu-S, Fu-P, and SC. Secondary outcomes included correlations across protein binding quartiles, serum albumin, and predicted in-hospital mortality, and identification of predictors for SC through multivariable analysis. RESULTS: Eighty-nine studies including 32 antimicrobials were included for analysis. SC was moderately correlated to Fu-S (R2 = 0.55, P < 0.001) and Fu-P (R2 = 0.41, P < 0.001). SC was best correlated to Fu-S in first (<69%) and fourth (>92%) quartiles of fraction unbound and above median albumin concentrations of 24.5 g/L (R2 = 0.71, P = 0.07). Conversely, correlation was weaker in patients with mortality estimates greater than the median of 55% (R2 = 0.06, P = 0.84). SC and Fu-P were also best correlated in the first quartile of antimicrobial fraction unbound (R2 = 0.66, P < 0.001). Increasing Fu-P, flow rate, membrane surface area, and serum albumin, and decreasing physiologic charge significantly predicted increasing SC. CONCLUSIONS: Fu-S and Fu-P were both reasonably correlated to SC. Caution should be taken when using Fu-S to calculate extracorporeal clearance in antimicrobials with 69%-92% fraction unbound or with >55% estimated in-hospital patient mortality. Fu-P may serve as a rudimentary surrogate for SC when Fu-S is unavailable.

Pharmacokinetic Evaluation of Cefazolin in the Cerebrospinal Fluid of Critically Ill Patients.

BACKGROUND: The relative distribution of cefazolin into the cerebrospinal fluid (CSF) remains debated. Determining the distribution of cefazolin into the CSF in noninfected adults may allow for further treatment applications of cefazolin. This prospective pharmacokinetic study aimed to determine the pharmacokinetic parameters of cefazolin in serum and CSF from external ventricular drains (EVDs) in neurologically injured adults. METHODS: Blood and CSF were collected, using a biologic waste protocol, for cefazolin quantification and trapezoidal rule-based pharmacokinetic analysis in a total of 15 critically ill adults receiving 2000 mg intravenously every 8 hours or the renal dose equivalent for EVD prophylaxis. RESULTS: A median (range) of 3 (2-4) blood and 3 (2-5) CSF samples were collected for each patient. The most common admitting diagnosis was subarachnoid hemorrhage (66.7%). The median calculated cefazolin CSF Cmax and Cmin values (interquartile range [IQR]) were 2.97 (1.76-8.56) mg/L and 1.59 (0.77-2.17) mg/L, respectively. The median (IQR) CSF to serum area under the curve ratio was 6.7% (3.7%-10.6%), with time-matched estimates providing a similar estimate (8.4%). Of those receiving cefazolin every 8 hours, the median and minimum directly measured CSF cefazolin concentration ≥4 hours following administration were 1.87 and 0.78 mg/L, respectively. CONCLUSIONS: Cefazolin dosed for EVD prophylaxis achieved CSF concentrations suggesting viability as a therapeutic option for patients with meningitis or ventriculitis due to susceptible bacteria such as methicillin-susceptible Staphylococcus aureus. Further clinical trials are required to confirm a role in therapy for cefazolin. Population-based pharmacokinetic-pharmacodynamic modeling may suggest an optimal cefazolin regimen for the treatment of central nervous system infections.

Evaluation of First-Dose, Intravenous Push Penicillins and Carbapenems in the Emergency Department.

BACKGROUND: Early appropriate antibiotic administration is associated with improved outcomes in infectious illnesses. During drug shortages in 2017, the American Society of Health-System Pharmacists recommended intravenous push (IVP) administration of medications when possible to conserve small-volume parenteral solutions. Data supporting IVP penicillins and carbapenems was limited. OBJECTIVE: The primary objective of this study compared time from patient emergency department (ED) arrival to antibiotic administration between IVP and intravenous piggy-back (IVPB) administration. METHODS: This single-center pre-post protocol study assessed changes in administration timing and safety of ampicillin/sulbactam, piperacillin/tazobactam, and ertapenem from 2015-2018. Medication administration by IVPB (pre) or IVP (post), ED arrival, antibiotic order and administration times, potential effectors of administration time, and safety events were assessed. Acquisition costs were estimated. RESULTS: A total of 696 administrations were included, with 351 and 345 subjects in the IVPB and IVP cohorts, respectively. The median time from ED arrival to initiation of antibiotic administration was 140 (IQR 87-221) minutes and 110 (IQR 68-181) minutes in the IVPB and IVP cohorts, respectively, (P < 0.01). IVP administration increased the proportion of indexed antibiotics administered within 60 minutes of ED arrival compared to IVPB (20% vs. 12%, respectively, P < 0.01). There was no difference in adverse events between both cohorts. Supply acquisition cost savings totaled an more than $5,000 with the IVP protocol. CONCLUSION: IVP administration of ampicillin/sulbactam, piperacillin/tazobactam, and ertapenem improved times to initiation of empiric, first-dose antibiotics in the ED without an increase in adverse events, saving over $5,000 annually.

Evaluation of a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol in hospitalized patients with COVID-19.

Patients with COVID-19 are at higher risk of thrombosis due to the inflammatory nature of their disease. A higher-intensity approach to pharmacologic thromboprophylaxis may be warranted. The objective of this retrospective cohort study was to determine if a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol incorporating severity of illness, weight, and biomarkers decreased incidence of thrombosis in hospitalized patients with COVID-19. Included patients were hospitalized with COVID-19 and received thromboprophylaxis within 48 h of admission. Exclusion criteria included receipt of therapeutic anticoagulation prior to or within 24 h of admission, history of heparin-induced thrombocytopenia, extracorporeal membrane oxygenation, pregnancy, or incarceration. Per-protocol patients received thromboprophylaxis according to institutional protocol involving escalated doses of anticoagulants based upon severity of illness, total body weight, and biomarker thresholds. The primary outcome was thrombosis. Secondary outcomes included major bleeding, mortality, and identification of risk factors for thrombosis. Of 1189 patients screened, 803 were included in the final analysis. The median age was 54 (42-65) and 446 (55.5%) were male. Patients in the per-protocol group experienced significantly fewer thrombotic events (4.4% vs. 10.7%, p = 0.002), less major bleeding (3.1% vs. 9.6%, p < 0.001), and lower mortality (6.3% vs. 11.8%, p = 0.02) when compared to patients treated off-protocol. Significant predictors of thrombosis included mechanical ventilation and male sex. Post-hoc regression analysis identified mechanical ventilation, major bleeding, and D-dimer ≥ 1500 ng/mL FEU as significant predictors of mortality. A targeted pharmacologic thromboprophylaxis protocol incorporating severity of illness, body weight, and biomarkers appears effective and safe for preventing thrombosis in patients with COVID-19.

Clinical Pharmacokinetics and Pharmacodynamics of Dalbavancin.

Dalbavancin is a synthetic lipoglycopeptide that exerts its antimicrobial activity through two distinct modes of action, inhibition of cell wall synthesis and an anchoring mechanism. Compared with previous glycopeptide antibiotics, dalbavancin demonstrates improved antibacterial potency against Gram-positive organisms and a long half-life of approximately 1 week, which is longer in tissues (e.g., skin, bone) than plasma. These factors facilitated the development of single-dose or once-weekly dosing regimens to treat acute bacterial skin and skin structure infections (ABSSSI). Dalbavancin exhibits dose-proportional pharmacokinetics and is highly protein bound (93%). Despite being highly protein bound, it has a steady-state volume of distribution >10 L and distributes widely into the skin, bone, peritoneal space, and epithelial lining fluid, but not cerebrospinal fluid. Dalbavancin elimination occurs via a combination of renal (approximately 45%) and non-renal clearance, with dose adjustments recommended only in patients with a creatinine clearance <30 mL/min not receiving any form of dialysis. The established pharmacokinetic/pharmacodynamic index associated with bacterial kill is free area under the concentration-time curve over the minimum inhibitory concentration (fAUC/MIC), with a goal 24-h fAUC/MIC of at least 27.1 for Staphylococcus aureus infections. Recent data suggest usefulness in the treatment of infections beyond ABSSSI, with convenient dosing and redosing strategies for complicated infections requiring extended treatment durations. Additional studies are needed to confirm these preliminary findings.

Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding.

The aim of this retrospective study was to compare andexanet alfa and 4-factor prothrombin complex (4F-PCC) for reversal of factor Xa (FXa)-inhibitor bleeding. Patients that received andexanet alfa for reversal were included. An equivalent number of patients administered 4F-PCC for FXa-inhibitor bleeding were randomly selected as historical controls. The primary outcome was effective hemostasis achievement within 12 h, defined using ANNEXA-4 criteria. Thromboembolic events and mortality within 30 days were also evaluated. A total of 32 patients were included. Baseline characteristics were not statistically different between andexanet alfa (n = 16) and 4F-PCC (n = 16). Intracranial bleeding was the primary reversal indication in 43.8% versus 62.5% of patients, respectively. Effective hemostasis was reached in 75.0% of andexanet alfa patients compared to 62.5% of 4F-PCC patients (P = .70). Thromboembolic events occurred in 4 (25.0%) patients and 3 (18.8%) patients, respectively (P = .99). Mortality incidence was 12.5% and 31.3%, respectively (P = .39). Andexanet alfa and 4F-PCC attained hemostasis in a majority of patients. A high, but a similar rate of thromboembolic events was seen with both treatments. Prospective studies are needed to elucidate comparative risks and benefits of the 2 agents.

A Severe Case of Diabetic Ketoacidosis and New-Onset Type 1 Diabetes Mellitus Associated with Anti-Glutamic Acid Decarboxylase Antibodies Following Immunotherapy with Pembrolizumab.

BACKGROUND Immune checkpoint inhibitors (ICIs) are a novel class of antibodies, which have been increasingly utilized in cancer immunotherapies. Pembrolizumab is a humanized IgG4 monoclonal antibody, which acts against programmed cell death (PD)-1 receptors to help restore the body's T-cell and immune response. CASE REPORT In this case, we present a 51-year-old woman with a past medical history of lung adenocarcinoma and triple-positive breast cancer who was actively receiving therapy with pembrolizumab. Following her second chemotherapy cycle, she developed a severe case of diabetic ketoacidosis (DKA), with concern for new-onset autoimmune type 1 diabetes mellitus (T1DM), secondary to her recent ICI therapy. The patient was initiated on a high-dose insulin infusion for rapid glycemic control and was successfully transitioned to a subcutaneous regimen approximately 24 h after presentation. She additionally developed other autoimmune-related complications, including hepatoxicity, duodenitis, and a maculopapular rash, which all resolved upon discontinuation of the ICI treatment. Her laboratory test results were consistent with positive anti-glutamic acid decarboxylase (anti-GAD) antibodies and undetectable c-peptides, illustrating the uniqueness of an ICI potentially precipitating an autoimmune T1DM. CONCLUSIONS Immune-related adverse events from ICI therapy warrant further investigation to acknowledge the risk of potentially life-threatening adverse reactions, such as the development of DKA. Patients receiving ICI therapy should be educated on signs and symptoms of hyperglycemia, and routine measurements of blood glucose levels should be completed during each chemotherapy cycle. Future research in assessing potential biomarkers of beta cell dysfunction, such as anti-GAD antibodies and c-peptides, is of interest, particularly for patients receiving ICI therapies.