Roles of Pharmacists in the Management of Sickle Cell Disease in Adults: A Narrative Review.

Background: Sickle cell disease (SCD) is an autosomal, recessive, genetic condition of the sickle cell genes. It affects about 100 000 people in the United States where an estimated 1 out of every 365 black children and 1 out of every 13 black children will be born with SCD and sickle cell trait, respectively. Severe and unpredictable pain crisis are the leading cause of emergency department visit for adult patients with SCD and account for 90% of inpatient hospitalizations and 85% of all acute medical care, as well as high usage of medical resources. The care of patients with SCD is complex and requires a multidisciplinary approach. With a few pharmacotherapeutic options to reduce SCD complications and pain episodes, the role of pharmacists in the medication management is unclear. This article aims to outline the potential role of pharmacists in SCD management. Data sources: The authors searched Medline, PubMed, EMBASE, and Scopus from January 1, 1990 to August 31, 2022, for primary literature that assessed the role of pharmacists in managing patients with SCD. Results: The authors identified relevant studies and summarized the role of pharmacists in SCD management. Conclusions: Access to comprehensive health care is essential to ensure that patients with SCD have decreased hospitalizations and good health-related quality of life. Pharmacists are an integral part of the multidisciplinary health-care team and can help patients with SCD navigate the complexities of health care. Pharmacists are medication experts who are positioned to ensure comprehensive care in the acute and chronic SCD management.

Piperacillin-tazobactam dosing in anuric acute kidney injury patients receiving continuous renal replacement therapy.

INTRODUCTION: To determine appropriate dosing of piperacillin-tazobactam in critically ill patients receiving continuous renal replacement therapy (CRRT). METHODS: The databases of PubMed, Embase, and ScienceDirect were searched. We used the Medical Subject Headings of "piperacillin-tazobactam," "CRRT," and "pharmacokinetics" or related terms or synonym to identify the studies for reviews. A one-compartment pharmacokinetic model was conducted to predict piperacillin levels for the initial 48 h of therapy. The pharmacodynamic target was 50% of free drug level above the minimum inhibitory concentration (MIC) and 4 times of the MIC. The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. RESULTS: Our simulation study reveals that the dosing regimen of piperacillin-tazobactam 12 g/day is appropriate for treating Pseudomonal infection with KDIGO recommended effluent rate of 25-35 mL/kg/h. The MIC values of each setting were an important factor to design piperacillin-tazobactam dosing regimens. CONCLUSION: The Monte Carlo simulation can be a useful tool to evaluate drug dosing in critically ill acute kidney injury patients receiving CRRT when limited pharmacokinetic data are a concern. Clinical validation of these results is needed.

Optimal Meropenem Dosing Regimens in Patients Undergoing Continuous Renal Replacement Therapy: Systematic Review and Monte Carlo Simulations.

INTRODUCTION: The optimal meropenem dosing regimens in critically ill patients receiving continuous renal replacement therapy (CRRT) based on pharmacokinetic and pharmacodynamic (PD) concepts are not well established. This study aimed to (1) gather the available published pharmacokinetic studies conducted in septic patients receiving CRRT and (2) to define the optimal meropenem dosing regimens in these populations via Monte Carlo simulations. METHODS: We used Medical Subject Headings "meropenem," "continuous renal replacement therapy," and "pharmacokinetics" or related terms to identify studies for systematic review. A one-compartment pharmacokinetic model was conducted to predict meropenem levels for the initial 48 h of therapy. The PD targets were 40% of free drug above a threshold of 1 times the minimum inhibitory concentration (MIC) (40% fT > MIC), 4 times the MIC (40% fT > 4MIC), and an additional target of free drug level above 1 times MIC 100% of the time (fT > MIC). The dose that achieved at least 90% of the probability of target attainment (PTA) was defined as an optimal dose. RESULTS: Twenty-one articles were included for our systematic review. The necessary pharmacokinetic parameters such as volume of distribution and CRRT clearance were cited in 90.5 and 71.4% of articles, respectively. None of the published studies reported completed necessary parameters. A regimen of 750 mg q 8 h was found to be the optimal dose for pre-dilution continuous venovenous hemofiltration and continuous venovenous hemodialysis modality using two effluent rates (25 and 35 mL/kg/h) which achieved the PD target of 40% fT > 4MIC. CONCLUSION: None of the published studies showed the necessary pharmacokinetic parameters. PD target significantly contributed to meropenem dosage regimens in these patients. Differing effluent rates and types of CRRT shared similar dosing regimens. Clinical validation of the recommendation is suggested.

Levetiracetam dosing in patients receiving continuous renal replacement therapy.

OBJECTIVE: The study was aimed to define appropriate levetiracetam dosing regimens from available published pharmacokinetics (PK) studies in critically ill patients with and without cirrhosis receiving continuous renal replacement therapy (CRRT) via Monte Carlo simulation (MCS). METHODS: Mathematical pharmacokinetic models were developed using published demographic and PK data in adult critically ill patients with known variability and correlations between PK parameters. CRRT modalities (continuous venovenous hemofiltration and continuous venovenous hemodialysis) with different effluent rates were modeled. Levetiracetam regimens from available clinical resources were evaluated on the probability of target attainment (PTA) using pharmacodynamics (PD) target of the trough concentrations and area under the time-concentration curve within a range of 6-20 mg/L and 222-666 mg × hour/L for the initial 72 hours of therapy, respectively. Optimal regimens were defined from regimens that yielded the highest PTA. Each regimen was tested in a group of different 10,000 virtual patients. RESULTS: Our results showed the optimal levetiracetam dosing regimen of 750-1000 mg every 12 hours is recommended for adult patients receiving both CRRT modalities with two different effluent rates of 25 and 35 mL/kg/h. Child-Pugh class C cirrhotic patients undergoing CRRT required lower dosing regimens of 500-750 mg every 12 ours due to smaller non-renal clearance. Of interest, some of literature-based dosing regimens were not able to attain the PK and PD targets. SIGNIFICANCE: Volume of distribution, non-renal clearance, CRRT clearance, and body weight were significantly correlated with the PTA targets. Dosing adaptation in this vulnerable population should be concerned. Clinical validation of our finding is absolutely needed.

Intraperitoneal daptomycin dosing for peritonitis may be inadequate: a Monte Carlo simulation approach to optimize dosing and outcomes.

A two-compartmental mathematical pharmacokinetic model with first-order elimination of patients receiving CAPD of 4 exchanges for 6 h with 2 L of dialysate used in each cycle was developed to predict daptomycin disposition in 120 h of therapy. The pharmacodynamic target was plasma AUC/MIC equal to or greater than 666. The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. Administering intraperitoneal 300 mg daily for 1 exchange daily regimen would be sufficient to treat peritonitis with S. aureus infection with MICs of 0.25 mg/L in patients undergoing CAPD. A higher dosage may be required for infections with a higher minimum inhibitory concentration. Pharmacodynamic targets and MICs significantly contributed to daptomycin doses in this setting. Clinical validation of our recommendations is recommended.

Contemporary Management and Prevention of Vaso-Occlusive Crises (VOCs) in Adults With Sickle Cell Disease.

Sickle cell disease (SCD) is a hematological disorder that primarily affects individuals of African descent from sub-Saharan Africa and along the mediterranean. The main complications leading to hospitalizations include vaso-occlusive crises (VOCs) and acute chest syndrome (ACS). Therefore, the main objective of this paper was to identify and evaluate evidence-based management and prevention of VOCs in patients with SCD. A literature search of PubMed, Medline Cochrane and Google Scholar database (January 1985 to April 2020) was performed using the following search terms "vaso-occlusive crises", "sickle cell disease", "hydroxyurea", "L-glutamine", "voxelotor", "crizanlizumab", "treatment" and "prevention" as well as a combination of these terms. All English-language interventional studies assessing the efficacy and safety of VOC outcomes were evaluated. Literature was excluded if published in a language other than English or if it was a review article. A total of 69 articles were identified and there were 7 articles that met the search criteria. Majority of the studies focused on mean and median annual rates of VOCs as primary outcomes while median time to first sickle cell crises, median rates of hospitalizations etc were evaluated as secondary outcomes. After reviewing the literature, many patients with VOCs will still benefit from hydroxyurea therapy since long term efficacy data and cost is still a concern for the newer agents including L-glutamine, voxelotor and crizanlizumab. Other factors such as cost or compliance may also be taken into consideration when making recommendations for therapy.

Alternatives to Hydrocortisone for Hemodynamic Support in Septic Shock Management Due to Medication Shortage.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. Septic shock is when initial fluid resuscitation fails to increase the mean atrial pressure to greater than or equal to 65 mm Hg. The 2021 Surviving Sepsis Campaign guidelines recommend corticosteroids for vasopressor and fluid-refractory septic shock patients. Medication shortages can arise, and their etiologies include natural disasters, quality control issues, and manufacturing discontinuation. The U.S. Food and Drug Administration and the American Society of Health-System Pharmacists announced a shortage of IV hydrocortisone. Methylprednisolone and dexamethasone are considered therapeutic alternatives to hydrocortisone. This commentary aims to guide clinicians on the alternative to hydrocortisone among septic shock patients due to medication shortage.

Lacosamide dosing in patients receiving continuous renal replacement therapy.

BACKGROUND: Lacosamide is one of the anticonvulsants used in critically ill patients. This study aimed to suggest appropriate lacosamide dosing regimens in critically ill patients receiving continuous renal replacement therapy (CRRT) via Monte Carlo simulations. METHODS: Mathematical models were created using published demographic and pharmacokinetics in adult critically ill patients. CRRT modalities with different effluent rates were added into the models. Lacosamide regimens were evaluated on the probability of target attainment (PTA) using pharmacodynamic targets of trough concentrations and area under the curve within a range of 5-10 mg/L and 80.25-143 and 143-231 mg*h/L for the initial 72 h-therapy, respectively. Optimal regimens were defined from regimens that yielded the highest PTA. Each dosing regimen was tested in a group of different 10,000 virtual patients. RESULTS: Our results revealed the optimal lacosamide dosing regimen of 300-450 mg/day is recommended for adult patients receiving both CRRT modalities with 20-25 effluent rates. The dose of 600 mg/day was suggested in higher effluent rate of 35 mL/kg/h. Moreover, a patient with body weight > 100 kg was less likely to attain the targets. CONCLUSIONS: Volume of distribution, total clearance, CRRT clearance and body weight were significantly contributed to lacosamide dosing. Clinical validation of the finding is strongly indicated.

The 2022 human monkeypox outbreak: Clinical review and management guidance.

PURPOSE: The objective of this clinical review is to provide an overview of antiviral therapies for monkeypox treatment and summarize the role of vaccines in monkeypox prevention. SUMMARY: The human monkeypox virus is a double-stranded DNA virus of the Orthopoxvirus genus of the Poxviridae family. The estimated case fatality rate for monkeypox ranges between 0% and 11%. The first human monkeypox infection was reportedly due to an unidentified animal reservoir. Per the Centers for Disease Control and Prevention, isolation and infection control procedures should be followed in the care of those infected with monkeypox virus. Monkeypox virus infection symptoms include rash, fever, chills, headache, muscle aches, backache, and fatigue that may progress to exhaustion. Severe complications such as encephalitis, pneumonia, and retropharyngeal abscess could appear in immunocompromised or critically ill patients. There are currently no specific Food and Drug Administration (FDA)-approved therapies for monkeypox. As with most viral infections, supportive care is the backbone of monkeypox clinical management. However, therapies effective for smallpox, such as cidofovir, brincidofovir, and tecovirimat, have previously been reported to be effective in the management of monkeypox. Pre- and postexposure prophylaxis to prevent monkeypox transmission are recommended in the US for those at high risk for disease transmission. CONCLUSION: There are no FDA-approved treatments for monkeypox infection. Surveillance and detection of monkeypox among high-risk populations should be implemented to help understand the epidemiology of this disease.

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors Use among Heart Failure Patients and the Role of Pharmacists in Early Initiation of Therapy.

Heart failure (HF) is a growing major public health and economic concern in the United States and worldwide. Heart failure mortality rates can be as high as 75% despite advances in therapies. HF is expected to be the fastest growing among all cardiovascular diseases, with HF-associated direct medical costs projected to nearly double over the next 10 years. Hospital admissions, re-admission, and medical cost are a huge burden to the healthcare system, and this is estimated to have increased gradually over the past decades despite the available advances in HF treatment and prevention. Many heart failure therapies have shown improvement in terms of mortality, morbidity, and symptomatic management. Guideline-directed medical therapy (GDMT) for heart failure has proven its ability to reduce morbidity and mortality by 66%. GDMT is recommended to be used among all HF patients when appropriate. In recent years, two new drug classes, angiotensin receptor-neprilysin inhibitor (ARNi) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, were approved by the United States Food and Drug Administration (US FDA) for the management of heart failure. The exact mechanism by which the SGLT-2 inhibitors attenuate the inflammatory process remains unclear. Several mechanisms have been suggested related to the cardiovascular benefit of SGLT-2 inhibitors, including a reduction in inflammation, improvement in natriuresis/diuresis, and promotion of the use of ketones as a secondary energy source. Clinical data showed that SGLT-2 inhibitors have morbidity and mortality benefits within 30 days of initiation. Studies have proven that clinical pharmacists practicing in HF inpatient and outpatient settings resulted in a reduction of HF hospitalization and an increase in the uptake of GDMT by initiating or up-titrating GDMT agents as well as providing patient education.

Kidney Function Assessment in African American Patients: A Narrative Review for Pharmacists.

Recent recognitions of longstanding societal inequity in kidney function assessments have prompted the call to eliminate race as part of the algorithm to assess estimated glomerular filtration rate (eGFR). Previous equations for eGFR estimation adopted race as part of the calculation. Incorporating race within eGFR equations results in overestimating and underestimating Black and nonblack patients, respectively. The inclusion of race is controversial. In September 2021, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) combined task force recommended estimating the kidney function without using a race variable. The task force endorsed race-free creatinine-cystatin C equations to be more accurate than the creatinine-only equations. Before the application of NKF-ASN revised recommendations, major healthcare disparities influenced daily clinical practice. Those disparities include the delay in initiating medications that have reanl or cardio-protective effects, such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and angiotensin-converting enzyme inhibitors (ACEIs). Clinical judgment should be employed when dose adjusting medications. Combining the eGFR with other clinical assessment tools such as urinary output, the expanded use of confirmatory tests, and the eGFR trend is suggested for a better kidney function assessment. Additionally, creatinine-cystatin C is recommended when feasible, and when institutions have the laboratory abilities.

Rates of Opioid Misuse Amongst Patients Receiving Pain Management for Sickle Cell Disease in An Urban Setting.

Background and Objective: Sickle Cell Disease (SCD) is known to cause acute severe pain episodes known as vaso-occlusive crisis (VOC) mainly treated with opioid analgesics. Since the opioid epidemic there is an interest in determining the opioid misuse potential in these patients. Therefore, the primary objective of this study is to determine the rates of opioid misuse among patients with SCD by assessing the rate of unexpected drug screening results in a sickle cell disease clinic. Methods: This was a retrospective chart review study conducted at the outpatient sickle cell disease clinic. The primary independent variables were the prescribed opioid medications while the primary dependent variable was the collected opioid metabolite. Descriptive statistics, linear regression and multivariate logistic regression analysis were conducted using SPSS version 24. Results: A total of 100 participants were recruited from July 1, 2018, to June 30, 2020 with 71 included in the analysis. The total mean of morphine milligram equivalents (MME) for all participants was 71.1±104.9 with 71% of participants having a daily calculated MME of <90MME. The odds of misusing an opioid were 6.72 times higher (P<.02) if a participant used marijuana compared to a participant who didn't. In addition, the odds of misusing an opioid were 2.47 times higher (P<.04) if the patient was prescribed an opioid daily dose greater than 90 MME as opposed to a daily dose less than 90 MME. Conclusion: Participants who consumed greater than 90 MME's per day and utilized marijuana were more likely to misuse opioids.

Creating a Machine Learning Tool to Predict Acute Kidney Injury in African American Hospitalized Patients.

Machine learning (ML) has been used to build high-performance prediction models in the past without considering race. African Americans (AA) are vulnerable to acute kidney injury (AKI) at a higher eGFR level than Caucasians. AKI increases mortality, length of hospital stays, and incidence of chronic kidney disease (CKD) and end-stage renal disease (ESRD). We aimed to establish an ML-based prediction model for the early identification of AKI in hospitalized AA patients by utilizing patient-specific factors in an ML algorithm to create a predictor tool. This is a single-center, retrospective chart review. We included participants 18 years or older and admitted to an urban academic medical center. Two hundred participants were included in the study. Our ML training set provided a result of 77% accuracy for the prediction of AKI given the attributes collected. For the test set, AKI was accurately predicted in 71% of participants. The clinical significance of this model can lead to great advancements in the care of AA patients and provide practitioners avenues to optimize their therapy of choice in AAs when given AKI risk ahead of time.

Comparative incidence of acute kidney injury in patients on vancomycin therapy in combination with cefepime, piperacillin-tazobactam or meropenem.

Recent studies have shown that the incidence of nephrotoxicity increases when vancomycin is combined with a beta-lactam antibiotic. The objective of this study was to compare the incidence of acute kidney injury (AKI) in adult patients who received vancomycin with either piperacillin-tazobactam (VPT), cefepime (VC), or meropenem (VM). This was a single center retrospective chart review. Patients were included if they were 18 years or older, received 48 hours of combination therapy and antibiotics were started within 24 hours of each other. Exclusion criteria were receiving more than one combination of antibiotics, serum creatinine > 1.2 mg/dL, AKI at the time of inclusion, or any form of renal replacement therapy. Two hundred patients met inclusion criteria. A total of 27 (13%) patients experienced AKI. The incidence of AKI was 21.6%, 9%, and 7.4% in the VPT, VC and VM groups, respectively. A patient who received VPT was 5 times more likely to develop AKI when compared to a patient who received VC (adjusted OR 5.09 95% CI (1.51-17.08), p = 0.008) and 7 times more likely to develop AKI when compared to VM (adjusted OR 7.03 95% CI (1.97-28.08), p = 0.002). This study found a statistically significant difference in the incidence of AKI in patient receiving VPT when compared to VC or VM. This finding supports the need for careful monitoring of renal function in patients receiving VPT therapy and routine evaluation for de-escalation of antimicrobial therapy.

The risks and benefits of early venous thromboembolism prophylaxis after elective spinal surgery: A single-centre experience.

BACKGROUND: There is a wide ranging incidence of venous thromboembolism after surgery and it continues to be a major cause of morbidity after spinal procedures.This study's aim was to investigate the relationship between timing and administration of venous thromboembolism (VTE) pharmacologic chemoprophylaxis after spinal surgery and the resulting VTE and bleeding complications by reviewing current practices and outcomes at a high-volume single institution to better define opportunities for perioperative intervention to prevent VTE without increasing bleeding complications. METHODS: All patients who underwent elective one or two-stage lumbar spinal fusion procedures were identified. A logistic regression was used to evaluate (1) risk of symptomatic VTE within 30 days of surgery and (2) bleeding-related complications. The odds of developing a VTE as well as bleeding-related complications were compared among the three treatment groups: no chemoprophylaxis, chemoprophylaxis < 24h of surgery and chemoprophylaxis given > 24h post-surgery. RESULTS: When adjusted for doses administered, the odds of developing a postoperative VTE within 30 days were 0.189 (95% confidence interval (0.044, 0.808)) in patients who received anticoagulation < 24h postoperatively, compared to those who received no anticoagulation (p = 0.025). There was no difference in bleeding rates. CONCLUSION: Patients undergoing elective spinal surgery who received anticoagulation within 24h of the conclusion of their procedure had an 81% reduction in the odds of developing a deep vein thrombosis within 30 days with no significant difference in bleeding complications.

Optimal levofloxacin dosing regimens in critically ill patients with acute kidney injury receiving continuous renal replacement therapy.

PURPOSES: To determine appropriate dosing of levofloxacin in critically ill patients receiving continuous renal replacement therapy (CRRT). METHODS: All necessary pharmacokinetic and pharmacodynamic parameters from critically ill patients were obtained to develop mathematical models with first order elimination. Levofloxacin concentration-time profiles were calculated to determine the efficacy based on the probability of target attainment (PTA) of AUC24h/MIC ≥50 for Gram-positive and AUC24h/MIC ≥125 for Gram-negative infections. A group of 5000 virtual patients was simulated and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the dose achieved target PTA at least 90% of the virtual patients. RESULTS: No conventional, FDA approved regimens achieved at least 90% of PTA for Gram-negative infection with Pseudomonas aeruginosa at MIC of 2 mg/L. The successful dose (1750 mg on day 1, then 1500 mg q 24 h) was far exceeded the maximum FDA-approved doses. For Gram-positive infections, a levofloxacin 750 mg q 24 h was sufficient to attain PTA target of ~90% at the MIC of 2 mg/L for Streptococcus pneumoniae. CONCLUSIONS: Levofloxacin cannot be recommended as an empiric monotherapy for serious Gram-negative infections in patients receiving CRRT due to suboptimal efficacy.

Meropenem dosing recommendations for critically ill patients receiving continuous renal replacement therapy.

PURPOSES: To gather available meropenem pharmacokinetics and define drug dosing regimens for Asian critically ill patients receiving CRRT. METHODS: All necessary pharmacokinetic and pharmacodynamic data from Asian population were gathered to develop mathematic models with first order elimination. Meropenem concentration-time profiles were calculated to evaluate efficacy based on the probability of target attainment (PTA) of 40%fT>4MIC. A group of 5000 virtual patients was created and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the doses achieved at least 90% of the PTA. RESULTS: The recommended meropenem dosing regimen for Asian critically ill patients receiving CRRT with standard (20-25 mL/kg/h) and high (35 mL/kg/h) effluent rates was 750 mg q 8 h to manage Gram negative infections with expected MIC < 2 mg/L in virtual Asian patients. Some meropenem dosages from available clinical resources could not achieve the aforementioned target. The volume of distribution, body weights and nonrenal clearance significantly contributed to drug dosing adaptation especially in the specific population. CONCLUSIONS: A meropenem regimen of 750 mg q 8 h was recommended for Asian critically ill patients receiving 2 different CRRT modalities with standard and high effluent rates. Clinical validation of these results is needed.

Antiviral Dosing Modification for Coronavirus Disease 2019-Infected Patients Receiving Extracorporeal Therapy.

Previous literature regarding coronavirus disease 2019 outlined a presence of organ dysfunction including acute respiratory distress syndrome and acute kidney injury that are linked to mortality. Several patients require extracorporeal therapy. This review aims to gather available published resources including physicochemical and pharmacokinetic properties and suggests antiviral drug dosing adaptation for coronavirus disease 2019-infected critically ill patients receiving extracorporeal therapy. A literature search was performed using PubMed, clinical trial registries, and bibliographic review of textbooks and review articles. Unfortunately, no standard of pharmacologic management and recommendations of drug dosing for coronavirus disease 2019 infection for critically ill patients receiving extracorporeal therapy exist due to the limited data on pharmacokinetic and clinical studies. All available extracted data were analyzed to suggest the appropriate drug dosing adjustment. Antiviral drug dosing adjustments for critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy are presented in this review. Considering pathophysiologic changes, drug properties, and extracorporeal modalities, applying our suggestions is recommended.