Showing papers in "American Journal of Therapeutics in 2018"
TL;DR: Clozapine rechallenge is a reasonable clinical option after return to baseline for patients who had developed neutropenia and neuroleptic malignant syndrome, but not after agranulocytosis or myocarditis.
Abstract: Background Clozapine is widely prescribed for treatment-refractory schizophrenia, but its use is limited by many potentially life-threatening adverse effects. The risk of rechallenge after these complications has never been comprehensively assessed in controlled studies. Thus, clinical guidelines must rely on the published case reports. The number of such reports is likely to increase over time, and updated analyses of larger samples are needed, as they may lead to changes in clinical guidelines. Study questions How safe is the clozapine rechallenge after life-threatening adverse effects? Study design The published case reports of clozapine rechallenge were identified in a MEDLINE search. We added 121 cases reported from 2012 through 2017 to the 138 cases reported from 1972 through 2011 analyzed by us in a previous publication. The 95% confidence intervals (CIs) of the successful rechallenge rate were calculated for each adverse effect with at least 5 published case reports. The rechallenge was considered a valid clinical option when the lower end of the CI range was at least 50%. Results A successful outcome was documented in 128/203 patients rechallenged after neutropenia (63.0%, CI, 56.0%-69.6%), 3/17 after agranulocytosis (17.7%, CI, 4.7%-44.2%), 11/17 after myocarditis (64.7%, CI, 38.6%-84.7%), and 7/7 after neuroleptic malignant syndrome (100%, CI, 56.1%-100%). Among the 15 patients with other clozapine-induced adverse effects, the rechallenge was successful in those with eosinophilia, cardiac complications other than myocarditis (QTc prolongation, pericarditis, cardiomyopathy, and atrial flutter), and gastrointestinal hypomotility. The rechallenge failed in patients who had developed pancreatitis or renal insufficiency. Conclusion Clozapine rechallenge is a reasonable clinical option after return to baseline for patients who had developed neutropenia and neuroleptic malignant syndrome, but not after agranulocytosis or myocarditis. Data are insufficient to formulate rechallenge guidelines for any other clozapine-related adverse effects.
53 citations
TL;DR: Telmisartan can better improve IR compared with other ARBs and is superior in improving homeostasis model assessment of insulin resistance.
Abstract: Background Diabetes mellitus, metabolic syndrome, and other obesity-related diseases are characterized by insulin resistance (IR) as a common pathophysiological change and are closely related to cardiovascular disease, which seriously threaten human health. Telmisartan belongs to a group of drugs called angiotensin II receptor antagonists (ARBs) and it can partially activate peroxisome proliferator-activated receptors. Animal experiments have confirmed that telmisartan can regulate glucose and lipid metabolism, and improve IR. Study question This study performs a systematic review of the advantages of telmisartan in improving IR and compared it with other ARBs. Study design Randomized controlled trials (RCTs) that compared telmisartan with other ARBs in patients with obesity, diabetes, impaired glucose tolerance, and metabolic syndrome were searched from PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, Wan Fang Database, and Chinese biomedical literature database (CBM). RCTs published as of the end of April 2017 were included in the present study. Measures and outcomes The outcomes included homeostasis model assessment of insulin resistance, fasting blood glucose level, fasting insulin level, diastolic blood pressure, and systolic blood pressure. We used a fixed-effects model or random-effects model to pool the estimates according to the heterogeneity between the included studies. Results A total of 21 RCTs, which included 1679 patients, were included. Results revealed that telmisartan was superior in improving homeostasis model assessment of insulin resistance (mean difference = -0.23, 95% confidence interval [CI], -0.40 to -0.06), reducing fasting blood glucose level (mean difference = -0.32, 95% CI, -0.57 to -0.07), reducing fasting insulin level (mean difference = -1.01, 95% CI, -1.63 to -0.39), and decreasing diastolic blood pressure (mean difference = -1.46, 95% CI, -2.10 to -0.82) compared with other ARBs. However, for the decrease in systolic pressure, the difference was not statistically significant (mean difference = -0.73, 95% CI, -1.53 to 0.07). Conclusion Telmisartan can better improve IR compared with other ARBs.
22 citations
TL;DR: A 70-year-old man with hypertension on amlodipine for many years and osteoarthritis on oxycodone presented with jaundice and was diagnosed with herbinduced liver injury with cholestasis and clinically improved with supportive care, however, he was readmitted 3 days later with worsening weakness and pruritus.
Abstract: A 70-year-old man with hypertension on amlodipine for many years and osteoarthritis on oxycodone presented with jaundice. He reported nausea, fatigue, profound weakness, and 9 kg of weight loss over 3 weeks, but denied fever, chills, vomiting, abdominal pain, diarrhea, and overt gastrointestinal bleeding. He was afebrile, hemodynamically stable, and had no encephalopathy. He had no personal or family history of liver disease. He denies excessive alcohol use. Initial blood work revealed white blood cell count of 12.1 K/mL, hemoglobin 10.4 g/dL, platelets 508 K/mL, international normalized ratio 1.4, blood urea nitrogen 80 mg/dL, and creatinine 2.27 mg/dL. His total bilirubin on presentation was 33.7 mg/dL, direct bilirubin 27 mg/dL, alkaline phosphatase 230 U/L, aspartate aminotransferase 53 U/L, and alanine aminotransferase 59 U/L. The patient reported a history of consumption of the herbal product kratom (Mitragyna speciosa) for pain twice daily for 4 days. This occurred approximately 2 to 3 weeks before his initial presentation with jaundice at another medical center, where he was found to have a total bilirubin of 41 mg/dL. The extensive workup for acute viral hepatitis, various liver diseases, and jaundice was negative, and computed tomography and magnetic resonance imaging of the abdomen with magnetic resonance cholangiopancreatography were unrevealing. Renal ultrasound revealed mildly increased renal cortical echogenicity but no hydronephrosis. The Roussel Uclaf Causality Assessment Method showed liver injury that was highly probable to be due to kratom.1,2 He was diagnosed with herbinduced liver injury with cholestasis and clinically improved with supportive care. However, he was readmitted 3 days later with worsening weakness and pruritus, as well as melena, and syncope. He was found to have profound anemia with hemoglobin of 4.8 g/dL and worsening creatinine of 2.94 mg/dL. He required 3 units of packed red cell transfusion. An esophagogastroduodenoscopy revealed a 1-centimeter nonbleeding duodenal ulcer and Helicobacter pylori was negative. He again denied nonsteroidal antiinflammatory drug use. A colonoscopy was unrevealing except for diverticulosis. The total bilirubin was 17.8 mg/dL on readmission and improved to 15.7 mg/dL. The elevated creatinine downtrended to 2.05 mg/dL after hydration. The abnormal liver tests, hyperbilirubinemia, and anemia normalized 3 months later and creatinine remained mildly elevated at 1.8 mg/dL. The cause of acute liver injury with cholestasis was attributed to kratom. Acute kidney injury of unclear mechanism was postulated from acute tubular necrosis secondary to pigment nephropathy from hyperbilirubinemia.
22 citations
TL;DR: The early post-discharge period, termed the "vulnerable phase" (VP), is associated with an increased risk of readmission and mortality, with rates of 30% and 10%, respectively, within the first few weeks as mentioned in this paper.
Abstract: The heart failure population is ever expanding, with approximately 23 million people worldwide diagnosed with heart failure (HF). In the United States, acute HF (AHF) accounts for more than 1 million hospital admissions.1–3 Despite improvements in morbidity and mortality for patients with chronic HF with reduced ejection fraction (EF) due to pharmacological and device-based therapies, rates of admission, readmission, and mortality remain high. Overall, in-hospital mortality is relatively low; it is the early postdischarge period, termed the “vulnerable phase” (VP), where the greatest number of adverse outcomes occurs (Figure 1). The VP begins with an AHF exacerbation and lasts up to 6 months postdischarge. Patients who survive this 6-month period after AHF represent a uniform cohort without significant variability among clinical profiles or systolic blood pressure classifications at the time of admission, thus suggesting an end point for the VP.4 This VP period is associated with an increased risk of readmission and mortality, with rates of 30% and 10%, respectively, within the first few weeks.5 Such poor outcomes may be attributed to cardiac factors (such as myocardial infarctions, atrial fibrillation, and uncontrolled hypertension), noncardiac comorbidities (such as diabetes, chronic obstructive pulmonary disease, and infection), patient-related factors (medication nonadherence, alcohol and substance abuse, dietary indiscretions), and system-based factors (such as poor access to discharge follow up).6 Additionally, the VP can be further categorized into 3 overlapping subphases: early, middle, and late phases. The very early VP includes the acute exacerbation and lasts upto the first few days after discharge. This was evident in the European Society of Cardiology Heart Failure Long-Term registry where 49% of patients admitted in cardiogenic shock died within the first 24 hours following presentation, illustrating the importance of early identification of hypoperfusion and appropriate in-hospital triage of these high risk patients.4 The early VP begins at the moment of discharge, and readmissions during this time frame have been attributed to both patientand system-related factors. The later VP takes into account all precipitating factors and comorbidities within 6 months of discharge7 (Table 1). As time progresses following a AHF, the readmission and mortality rates gradually decline, as highlighted in the Candesartan in Heart Failure: Assessment of Reduction on Mortality and Morbidity trial. Odds for mortality declined from 6-fold during the first month after discharge to 2-fold over the time of the trial.8 The susceptibility of patients during the VP presents a potential opportunity to improve patient outcomes by altering the trajectory of an otherwise poor prognosis.9
20 citations
TL;DR: A systematic review of the published case reports of clozapine-associated pulmonary embolism indicates that this adverse effect is highly lethal, has early onset and is dose independent.
Abstract: Background Recent epidemiological studies have identified an excess of pulmonary embolism (PE) cases in patients treated with antipsychotic drugs. The findings are particularly relevant for patients treated with clozapine, which has many potentially life-threatening adverse drug effects. Among these adverse drug effects are myocarditis and agranulocytosis that have early onset and are dose independent, but also seizures and myocardial repolarization delay, which are dose dependent and may occur at any time. Together with death rates, these variables have important implications for clinical practice. Areas of uncertainty Study Question: What are the time of onset, dose relationship, and mortality of clozapine-associated PE? Data sources The published case reports of clozapine-associated PE were identified in a MEDLINE search. Cases occurring within 6 months of starting clozapine were considered to have early onset. Dosages of clozapine at the time of PE were defined as low (200 mg/d or less) or high (300 mg/d or greater). Patient outcome was divided into survival of the PE event and death. Results The search identified 23 cases of clozapine-associated PE. The PE had early onset (6.4 ± 7.0 weeks) in 20 patients (87%, 95% confidence interval 67.9%-95.5%). PE occurred in 9 patients treated with low doses (152.8 ± 50.7 mg/d) and in 11 patients on high doses (372.7 ± 127.2 mg/d) of clozapine. Six patients (26.1%, 95% confidence interval 12.6%-46.5%) died. Conclusions A systematic review of the published case reports of clozapine-associated PE indicates that this adverse effect is highly lethal, has early onset and is dose independent. The findings should prompt careful monitoring and consideration of prophylactic treatment for venous thromboembolism for 6 months after starting treatment with clozapine.
17 citations
TL;DR: In this paper, a systematic approach is proposed that should start with admission and continue through post-discharge, as outcomes are influenced by many factors, many of which are incompletely understood.
Abstract: The global burden that acute heart failure (AHF) carries has remained unchanged over the past several decades.1 European registries2–5 showed that 1-year outcome rates remain unacceptably high (Table 1) and confirm that hospitalization for AHF represents a change in the natural history of the disease process.6 Because patients hospitalized for heart failure (HF) have a bad prognosis, it is crucial to use hospitalization as an opportunity to: (1) assess the individual components of the cardiac substrate; (2) identify and treat comorbidities; (3) identify early, safe end points of therapy to facilitate timely hospital discharge and outpatient follow-up; and (4) implement and begin optimization of guideline-directed medical therapies (GDMTs). As outcomes are influenced by many factors, many of which are incompletely understood, a systematic approach is proposed that should start with admission and continue through postdischarge.7 This review provides practical recommendations on HF management during the time of hospitalization and aims to summarize key lessons from clinical trials and registries in AHF (Table 2).
13 citations
TL;DR: Evidence is found that the conventional weight-based regimen of immune checkpoint inhibitors could potentially be beneficial from a financial standpoint without compromising the clinical outcomes.
Abstract: To the Editor: In 2016, the Food and Drug Administration modified the dosage regimen for nivolumab to a flat dose of 240 mg based on a pharmacokinetic analysis.1 Similarly, a flat dose of 200 mg of pembrolizumab was approved by the Food and Drug Administration to treat non–small-cell lung cancer based on the results of the KEYNOTE 024 study.2 Evidence suggests that pembrolizumab has equivalent efficacy whether a dose of 2 or 10 mg/kg is used.3 Recently, Goldstein et al4 have demonstrated that a flat dose of pembrolizumab over the standard weight-based regimen in first-line metastatic non– small-cell lung cancer leads to a significant financial burden. We performed a study to investigate whether a flat dose of nivolumab or pembrolizumab is associated with increased immune-related toxicity or financial burden compared with regular weight-based regimens. Our secondary objective was to assess whether the clinical efficacy differs between these 2 dosing regimens, as measured by overall survival. Our final analysis included 137 patients who were treated with nivolumab or pembrolizumab at the University of Oklahoma Health Sciences Center between 2014 and 2018. Patients who received both flat and weight-based dose of either agent were excluded from the analysis. Simple descriptive statistics were created for all covariates. Chi-square analysis was performed to compare the immune-related adverse events between the 2 groups. We calculated Kaplan–Meier survival curves, followed by a logrank test to compare survival. We then used Cox proportional hazards model to adjust for possible confounding variables. Finally, to determine the financial burden of these agents, we looked at the total dose received by patients treated with a flat dose and calculated the dose they would have received based on their weight (2 mg/kg for pembrolizumab and 3 mg/kg for nivolumab) to analyze the cost difference. The median age of patients was 61 years, and females comprised 53% of the study population. The median body weight and body mass index were 73 kg and 25 kg/m2, respectively. Lung cancer was the most common diagnosis (25%), followed by melanoma (20%). Pembrolizumab (50%) and nivolumab (50%) were used in a similar frequency. Most patients received a flat-dose treatment (64%). After adjustment for age, performance status, body mass index, cancer type, and line of treatment, there was no difference in overall survival by the dose type (P 5 0.28). The incidence of immune-related adverse events was similar across dose types after adjusting for age, body weight, performance status, cancer type, agent used, and line of therapy (P 5 0.08). Patients treated with flat-dose pembrolizumab received on average a total of 50.6 mg more per dose than they would have received with the weight-based dose (n 5 60) and those treated with flat-dose nivolumab received 3.4 mg less per dose (n 5 25). Average sales prices from the first quarter of 2015 show the average per-mg wholesale prices to be $28.78 for nivolumab and $51.79 for pembrolizumab. Taking this into consideration, we estimated that personalized dosing of these 2 drugs would have saved $1820.46 (Std dev $2606.91) per patient per course of treatment leading to a total savings of $642,877 over all courses of therapy. Using our single-institution database, we found evidence that the conventional weight-based regimen of immune checkpoint inhibitors could potentially be beneficial from a financial standpoint without compromising the clinical outcomes.
11 citations
11 citations
TL;DR: Efficacy was measured by the need for physical restraints and time to discharge and tolerability by recording all side effects, and clozapine therapy seemed beneficial in treatment-resistant agitation in patients with dementia.
Abstract: Background Behavioral and psychological symptoms in dementia significantly contribute to caregiver burden and impose patient hospitalization. The goal of treatment of admitted patients is the rapid remission of symptoms to allow their return to home as soon as possible. Intervention requires an intrusive approach with parenteral treatment and physical restraints, with a negative emotional impact on patients and their families. Despite the large utilization of antipsychotics for behavioral and psychological symptoms, there is no antipsychotic approved by the Food and Drug Administration for agitation in dementia. Study question To evaluate efficacy and tolerability of clozapine in patients with treatment-resistant agitation associated with dementia. Study design Cohort study with 337 patients, admitted between January 1, 2012 and December 31, 2016, with dementia according to The Diagnostic and Statistical Manual of Mental Disorders 4th ed. criteria. Clozapine was given in standard titration, starting with 6.25 or 12.5 mg. Measures and outcomes Efficacy was measured by the need for physical restraints and time to discharge and tolerability by recording all side effects. Data collected included demographics, psychotropics used, physical restraints, length of stay, destination after discharge, and comorbidities. Results Of 337 cases, 315 (93.5%) patients received antipsychotics. There were 27 cases treated with clozapine. Before clozapine initiation, haloperidol was given in 16 cases (55.17%, mean = 7.43 mg/d, SD = ±4.01), and the treatment was stopped mainly because of extrapyramidal side effects. Other antipsychotics used were quetiapine (mean dose = 260 mg/d, SD = ±54.77), risperidone (mean dose = 3.3 mg/d, SD = ±0.57), and olanzapine (mean dose = 8.33 mg/d, SD = ±2.88). Mean dose of clozapine was 59.16 mg/d, (SD = ±40.48), ranging from 12.5 to 200 mg/d. There were a lower number of physical restraints after clozapine initiation than before (12 vs. 34, P Conclusions Clozapine therapy seemed beneficial in treatment-resistant agitation in patients with dementia. The risk-benefit balance must be well weighed when clozapine is chosen. More studies are needed.
11 citations
TL;DR: This chapter discusses Duloxetine uses in patients with kidney disease: different recommendations from the United States versus Europe and Canada, and the impact of selective publication of antidepressant trials on apparent efficacy.
Abstract: 1. Nguyen T, Shoukhardin I, Gouse A. Duloxetine uses in patients with kidney disease: different recommendations from the United States versus Europe and Canada. Am J Ther. 2018 [epub ahead of print]. doi: 10.1097/MJT. 0000000000000737. 2. Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008; 358:252–260. 3. Sismondo S. Ghost management: how much of the medical literature is shaped behind the scenes by the pharmaceutical industry? PLoS Med. 2007;4:e286. 4. Available at: https://www.cbsnews.com/news/cassperwas-gsks-friendly-ghostwriting-program-on-paxil/. Accessed March 9, 2018. 5. Wiles NJ, Thomas L, Turner N, et al. Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial. Lancet Psychiatry. 2016;3:137–144. 6. Wernicke J, Pangallo B, Wang F, et al. Hepatic effects of duloxetine-I: non-clinical and clinical trial data. Curr Drug Saf. 2008;3:132–142. 7. Available at: http://www.fda.gov/Safety/MedWatch/ SafetyInformation/ucm255064.htm. Accessed March 9, 2018. 8. Safdieh JE, Rudominer R. A case of hyponatremia induced by duloxetine. J Clin Psychopharmacol. 2006;26:675–676. 9. Revol R, Rault C, Polard E, et al. Hyponatremia associated with SSRI/NRSI: descriptive and comparative epidemiological study of the incidence rates of the notified cases from the data of the French National Pharmacovigilance Database and the French National Health Insurance. Encephale. 2017 [epub ahead of print]. doi: 10.1016/j.encep.2017.09.003. 10. Available at: http://english.prescrire.org/en/81/168/52722/ 0/NewsDetails.aspx?page55. Accessed March 9, 2018. 11. Braillon A. Duloxetine: urinary incontinence and marketing authorization incontinence. CMAJ. 2017;189:E373. 12. Ioannidis JP. Evidence-based medicine has been hijacked: a report to David Sackett. J Clin Epidemiol. 2016;73:82–86.
11 citations
TL;DR: This paper presents a meta-analyses of the immune system’s response to infectious disease in Oklahoma City over a period of 12 months and shows clear patterns of infection and disease progression that are consistent with influenza.
Abstract: Department of Internal Medicine University of Oklahoma Oklahoma City, Oklahoma Department of Biostatistics and Epidemiology University of Oklahoma Oklahoma City, Oklahoma Department of Internal Medicine University of Oklahoma Oklahoma City, Oklahoma Department of Clinical Pharmacy Services University of Oklahoma Oklahoma City, Oklahoma Department of Biostatisctics and Epidemiology The University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma
TL;DR: Nivolumab alone or in combination with ipilimumab is a valid option for recurrent SCLC and pembrolizumab has been evaluated in a multicohort, phase 1b trial, and preliminary data showed a durable response in the second-line setting.
Abstract: Background Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer diagnoses each year. SCLC is characterized by a rapid doubling time, early metastatic spread, and an unfavorable prognosis overall. Areas of uncertainty Most patients with SCLC will respond to initial treatment; however, the majority will experience a disease recurrence and response to second-line therapies is poor. Immune checkpoint inhibitors may be an option given the success in other diseases. Data sources A literature search was conducted using Medline (1946-July week 1, 2017) and Embase (1996-2017 week 28) with the search terms small cell lung cancer combined with nivolumab or ipilimumab or pembrolizumab or atezolizumab or tremelimumab or durvalumab. Five clinical trials, including extended follow-up for 2, that evaluated immune checkpoint inhibitors in limited stage or extensive stage SCLC were included. Results In 2 phase 2 trials, ipilimumab was added to upfront chemotherapy. In both trials, an improvement in progression-free survival was seen. Toxicity, when combined with a platinum and etoposide, was significant. In a confirmatory phase 3 trial, ipilimumab did not prolong overall survival when added to first-line chemotherapy. Overall, response rates were similar between the placebo and ipilimumab groups. A phase 1/2 trial evaluated nivolumab alone or in combination with ipilimumab in recurrent SCLC. Results revealed that nivolumab monotherapy and the combination of nivolumab and ipilimumab were relatively safe and had antitumor activity. Pembrolizumab has been evaluated in a multicohort, phase 1b trial. Preliminary data showed a durable response in the second-line setting. Conclusion Given the lack of overall survival data and significant toxicity associated with the combination of ipilimumab with first-line chemotherapy, this treatment is not a reasonable option at this time. Nivolumab alone or in combination with ipilimumab is a valid option for recurrent SCLC.
TL;DR: This is a case of a 61-year-old man with a history of renal transplant secondary to hereditary nephritis with the uromodulin gene mutation who had been on chronic immunosuppressive therapy with mycophenolate and cyclosporine who presented to the emergency department with acute onset of nausea, vomiting, and worsening epigastric abdominal pain over 2 days.
Abstract: To the Editor: Tigecycline (Tygacil) is a glycylcycline antibiotic, which binds to the 30S ribosomal subunit and inhibits protein synthesis in susceptible bacteremia from a variety of gram-positive and gram-negative pathogens including methicillin-resistant staphylococci. Although tigecycline is known to have more common and significant gastrointestinal effects such as nausea, vomiting, and diarrhea, acute pancreatitis has been reported in very limited number of cases. This is a case of a 61-year-old man with a history of renal transplant secondary to hereditary nephritis with the uromodulin gene mutation who had been on chronic immunosuppressive therapy with mycophenolate and cyclosporine. Because of his immunosuppressive state, he developed a bilateral leg infection with nontuberculous Mycoplasma chelonae. After failing treatment with quinolones and linezolid, he was started on outpatient 6-month treatment with intravenous clofazimine and tigecycline. His leg infection cleared up significantly within 4 weeks after starting clofazimine and tigecycline. Although his soft tissue infection resolved with the use of antibiotics, he presented to the emergency department with acute onset of nausea, vomiting, and worsening epigastric abdominal pain over 2 days. On presentation, his temperature was 98.8 F, blood pressure 65/44 mm Hg, and heart rate 117 bpm. Laboratory test results showed a white blood cell count of 21,000 mL and a lipase level of 1835 U/L. Further workup with abdominal computed tomography showed findings consistent with acute pancreatitis. There was notably increased density and stranding of the adjacent peripancreatic fat, which extended toward the stomach and spleen and inferiorly toward the left pararenal fascia. At the tail of the pancreas, there was a heterogeneous mass-like appearance measuring 3.0 3 3.6 cm likely secondary to pancreatitis (Figure 1). The patient was admitted to the intensive care unit for sepsis secondary to acute pancreatitis. Other common causes of pancreatitis were excluded including gallstones, alcohol abuse, hypertriglyceridemia, hypercalcemia, and trauma. Tigecycline was discontinued, which subsequently caused a decrease in the lipase level to 450 U/L, with resolution of symptoms within 24–48 hours of discontinuation. Tigecycline is a known derivative of minocycline, which falls under the tetracycline class of drugs. Tetracyclines generally cause pancreatitis through the accumulation of toxic metabolites in the system, and it is possible that tigecycline may share similar side effects through a similar mechanism of action.1 In the few reported cases, tigecycline was almost always used to treat soft tissue infections similar to the case described above.2,3 In 1 reported case, tigecycline was used to treatMycoplasma chelonae bronchitis in a patient with known cystic fibrosis, which itself is a risk of pancreatitis.4 It is important to note that although the onset of symptoms after the use of tigecycline has been described after 5 days in the reported cases, it can
TL;DR: It is suspected that Entresto may cause angioedema of the gut and collagenous colitis, which are rare causes of bowel obstruction, and further studies should be conducted to determine whether EntrestO may increase the incidence of SBO or collagenous Colitis.
Abstract: distended small bowel loops were noted on computed tomography of the abdomen/pelvis. Exploratory laparotomy with distal small bowel resection was performed after identifying distal small bowel anastomosis stricture. Two days postoperatively, the patient complained of abdominal discomfort, nausea, and green fecaloid emesis. The patient was treated with nasogastric tube placement, enema, metoclopramide, intravenous fluids, and replacement of electrolytes. Computed tomography of the abdomen/pelvis revealed mildly dilated small bowel loops in the upper abdomen without evidence of free air or free fluid. At that time, we discontinued Entresto because of suspicion of intestinal angioedema in the setting of collagenous colitis, which might have been contributing to the SBO with significant improvement of symptoms after Entresto was discontinued. The patient recovered with conservative therapy. The differential of small bowel ileus in this patient includes adhesions, small bowel edema from congestive heart failure, and radiation enteritis causing SBO. The Naranjo score was 3, which correlates with adverse drug reaction. The risk of angioedema has been suggested with angiotensin receptor blockers as shown in several case reports. Angioedema has been reported in olmesartan medoxomil,2 a nonpeptide antagonist of the angiotensin II subtype 1 receptor causing significant swelling of the face, neck, and lips. Other case reports report angioedema with ARBs3–5 and with fixed-dose combination such as telmisartan plus ramipril, which is an ARB plus ACEI combination in the treatment of hypertension.6 The typical presentation is swelling of the lips, tongue, upper airway, whereas another presentation may be intermittent abdominal pain due to gastrointestinal angioedema. After an extensive review of the literature, we suspect that Entresto may cause angioedema of the gut and collagenous colitis, which are rare causes of bowel obstruction, and further studies should be conducted to determine whether Entresto may increase the incidence of SBO or collagenous colitis.
TL;DR: In an ICU patient receiving fentanyl, an unexplained worsening in chest wall compliance should prompt consideration of fentanyl-induced chest wall rigidity and serotonin syndrome in critically ill ICU patients.
Abstract: of anesthetic or analgesic doses of fentanyl.6,7 Fentanyl-induced chest wall rigidity has been reported in the neonatal, pediatric, and anesthesia literature.7 It is likely underdiagnosed in an ICU setting, as we could find only 1 other reported case in an ICU patient.7 Treatment includes reversal with naloxone in nonintubated patients and severe cases requiring ventilator support.6 Our patient was already intubated and chest wall compliance improved after discontinuation of fentanyl, similar to the other reported case in the literature.7 It is reported that this reaction does not preclude the future use of fentanyl, although caution is recommended.6 Naranjo scores were calculated for fentanylassociated chest wall rigidity and serotonin syndrome per the following: previous reported cases (+1), followed a reasonable temporal sequence after drug administration (+2), improvement with discontinuation (+1), and objective evidence (+1). A score of 5 was thus suggestive of fentanyl as the probable cause of both.8 Furthermore upon taking into account all other factors (clinical and drug induced), these reactions could not be attributed to another disease process. In conclusion, the recognition of fentanyl-induced chest wall rigidity and serotonin syndrome in critically ill ICU patients requires a high index of suspicion. In an ICU patient receiving fentanyl, an unexplained worsening in chest wall compliance should prompt consideration of fentanyl-induced chest wall rigidity. If associated with high-grade fevers, coexistence of serotonin syndrome should be considered. The at-risk population includes those receiving fentanyl who may have also been exposed to other serotonergic drugs. Treatment includes discontinuation of offending agents and aggressive supportive care. Jenna L. McGreevy, PharmD Samuel T. Piraino, BSPharm, BCPS Gagangeet Sandhu, MD Department of Pharmacy St Joseph’s Hospital Syracuse, NY Division of Critical Care Department of Medicine St Joseph’s Hospital Syracuse, NY
TL;DR: Multicomponent nonpharmacologic interventions are currently the most effective modality for the prevention and treatment of delirium.
Abstract: Background: Delirium is one of the most common, costly, and devastating complications affecting up to 56% of hospitalized older patients, with an associated hospital mortality rate of 25%–33%, and annual health care expenditures exceeding $152 billion. Areas of Uncertainty: Despite its high prevalence and poor outcomes, there is a significant gap in therapeutic interventions for the prevention and treatment of delirium. Therapeutic Interventions: Nonpharmacologic multicomponent prevention interventions such as the hospital elder life program (HELP) and early mobilization and reorientation remain first line, and they have consistently demonstrated a reduction in the incidence of delirium. There is currently no evidence to support the use of antipsychotics, cholinesterase inhibitors, or psychostimulants for the prevention of delirium across all health care settings, including the intensive care unit. Avoiding sedation, and specifically benzodiazepines, is an important modality to prevent delirium. Given the lack of evidence to support the use of antipsychotics along with the adverse event profile, including a black box warning for an increase in cardiovascular mortality, these medications should only be used for the treatment of delirium with features of severe agitation and psychosis. In the intensive care unit setting, dexmedetomidine in lieu of propofol or other classic sedatives may prevent and shorten the duration of delirium. Finally, dexmedetomidine and general anesthetics, such as sevoflurane and desflurane, are being evaluated in the prevention and treatment of postoperative delirium. Conclusion: Multicomponent nonpharmacologic interventions are currently the most effective modality for the prevention and treatment of delirium.
TL;DR: Patients with MDS/AML should be encouraged to enroll in clinical trials targeting this pathway as PD-1 pathway is an important target in MDS, and a single-agent nivolumab demonstrated excellent response to MDS in this patient.
Abstract: related pancytopenia, we held off on that regimen. She was started on nivolumab at a dose of 3 mg/kg of body weight every 2 weeks for mSCC of lung. After 2 cycles of nivolumab, she had normalization of her counts with a WBC of 4.11 K/mm3, absolute neutrophil count of 1.97 K/mm3, hemoglobin of 12.5 g/dL, and platelet count of 185 K/mm3. A CT scan of chest, abdomen, and pelvis showed partial response of her lung cancer. A repeat bone marrow biopsy showed 50%–60% cellularity. There was no increase in blasts. No significant dyspoiesis was present. Fluorescence in situ hybridization results were normal. Seven months after her initial presentation, she relapsed with AML. She was started on 5-azacitidine, and nivolumab was continued. Her lung cancer continued to respond to treatment. Her AML progressed after 4 cycles of 5-azacitidine, and she received anthracycline and cytarabine (5 + 2). She went into complete remission and received 1 cycle of consolidation cytarabine. Unfortunately, 19 months after her initial presentation, the patient died from an aortic dissection. She had no evidence of progression of her lung cancer or AML at the time of her death. This case demonstrates that PD-1 pathway can be an important target in MDS. A previous phase 1 study looked at the response of the PD-1 inhibitor Pidilizumab in patients with hematologic malignancies including 9 patients with AML/MDS. Only 1 patient had minimal response to treatment.2 This is in contrast to our finding where a single-agent nivolumab demonstrated excellent response to MDS in our patient. It has been shown that treatment with hypomethylating agents leads to enhanced expression of PD-L1, PD-L2, PD-1, and CTLA4 in MDS.3 Subsequently, it has led to several clinical trials combining hypomethylating agents with immunotherapy. The early results are promising with reported response rate of more than 30% in AML.4 In conclusion, PD-1 pathway is an important target in MDS/AML. Patients with MDS/AML should be encouraged to enroll in clinical trials targeting this pathway.
TL;DR: The present cases suggest that low-dose mirtazapine may be an appropriate medication in pregnant women with major depression secondary to HG and that depressive symptoms occurred after HG and showed improvement after treatment with mirtzapine at lower doses than what is recommended for antidepressant the antidepressant efficacy.
Abstract: To the Editor: Psychiatric disorders are frequently seen in patients with hyperemesis gravidarum (HG); however, the relationship between psychiatric disorders and HG is unclear. Some case reports have suggested mirtazapine to be beneficial for HG.1,2 The current report presents the benefit of low-dose mirtazapine in 7 women with major depression secondary to HG. The data were obtained from clinical registers of patients who were admitted to the perinatal psychiatry outpatient clinic of a university hospital. All the patients were referred from the obstetrics and gynecology inpatient clinic of the same hospital because of severe depressive and anxiety symptoms. All the patients had multiple hospitalizations due to the symptoms of HG and were nonresponsive to antiemetic medications. The patients were diagnosed by means of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).3 None of the patients had any comorbid mood or anxiety disorder. The severities of depressive and anxiety symptoms before and after the medication were assessed by using Hamilton Rating Scale for Depression (HAM-D)4 and Hamilton Rating Scale for Anxiety (HAM-A).5 Treatment response was defined as a decline of 50% or more in the HAM-D score after the administration of mirtazapine. The data were analyzed using the Statistical Package for the Social Sciences (SPSS), version 16.0, for Windows. The comparisons were performed with paired samples t test. The mean gestational age at the initiation of treatment with mirtazapine was 11.57 6 2.37 (range 5 7–14) weeks. The mean duration and dose of mirtazapine treatment were 9.14 6 7.47 (range: 4–24) weeks and 12.85 6 3.76 mg/d (range: 7.5–15 mg), respectively. Based on changes from baseline HAM-D score, all patients responded to the treatment. The HAM-D (23.85 6 6.33 vs. 3.28 6 2.21, t 5 10.11; P 5 0.000) and HAM-A (22.64 6 5.67 vs. 3.71 6 2.07, t 5 8.89, P 5 0.000) scores were significantly reduced after the treatment. Because of complete remission of the depressive symptoms, treatment was discontinued after 4 weeks in 3 women, 6–8 weeks in 2 women, and 14 weeks in 1 woman. One patient experienced recurrence in depressive symptoms and nausea/vomiting; therefore, mirtazapine administration was resumed during the pregnancy period. Other patients did not report any recurrence of depressive or HG symptoms in their follow-up period. None of the patients reported any incidence of hospitalization due to HG symptoms after their treatment with mirtazapine. In this report, we observed useful effects of mirtazapine in women with major depression secondary to HG. The mechanism of efficacy of mirtazapine on major depression in women with HG is unclear. In the current cases, depressive symptoms occurred after HG and showed improvement after treatment with mirtazapine at lower doses than what is recommended for antidepressant the antidepressant efficacy. Moreover, the nausea and vomiting symptoms of HG were concurrently resolved after the treatment. For this reason, 2 possible mechanisms may be proposed: first, improvement in major depressive disorder may be secondary to the mitigation of HG symptoms. Some authors have reported cases suggesting the benefits of mirtazapine as an alternative regimen in patients with severe HG resistant to conventional therapy.1,2 However, prospective studies have suggested that anxiety and depression were associated with HG rather than a cause of HG, and the psychological stress may decrease together with symptoms of HG.6,7 Second, mirtazapine may simultaneously alleviate the symptoms of both depressive or anxiety and HG. In conclusion, the present cases suggest that low-dose mirtazapine may be an appropriate medication in pregnant women with major depression secondary to HG. To determine specific effects of mirtazapine in this clinical condition, further controlled studies should be conducted.
TL;DR: Levetiracetam in children, adolescents and young adults with intractable epilepsy: efficacy, tolerability and effect on electroencephalogram–a pilot study.
Abstract: sound perception caused by carbamazepine. Intern Med. 2003;42:880–883. 4. Tateno A, Sawada K, Takahashi I, et al. Carbamazepineinduced transient auditory pitch-perception deficit. Pediatr Neurol. 2006;35:131–134. 5. Goldberg-Stern H, Feldman L, Eidlitz-Markus T, et al. Levetiracetam in children, adolescents and young adults with intractable epilepsy: efficacy, tolerability and effect on electroencephalogram–a pilot study. Eur J Paediatr Neurol. 2013;17: 248–253.
TL;DR: Syncope is a very rare side effect of pemetrexed. as mentioned in this paper reported that 2.2% of patients with nonsquamous small cell lung cancer were diagnosed with syncope.
Abstract: metabolizing enzymes including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase.2 Myelosuppression is a common side effect as folate metabolism is required for cell cycle progression. As such, pemetrexed can damage and decrease the overall amount of each cell line produced in the bone marrow. However, supplementation with folic acid and vitamin B12 has significantly decreased these side effects without a decreased efficacy in treatment.2 Other common side effects that can be seen from treatment with pemetrexed are nausea/vomiting, allergic reactions, renal impairment, liver damage, and cardiotoxicity. However, with careful monitoring, these side effects are also able to be avoided and/or kept in check. Therefore, this group of ailments tends to not severely affect the success of the chemotherapy treatment in each patient. Syncope is a very rare side effect of pemetrexed. In a recent study of 90 patients with nonsquamous non– small cell lung cancer being treated with pemetrexed, 2.2% developed syncope.1 Although the exact pathophysiology of syncope secondary to pemetrexed use is largely unknown, it is believed to be a possible sequelae of coexisting pemetrexed-induced cardiotoxicity. Therefore, treatment is cessation of pemetrexed with conversion to a different chemotherapeutic agent.
TL;DR: Theophylline pharmacokinetics during acute respiratory viral illness,therapeutic index drugs.
Abstract: therapeutic index drugs. Accessed December 2013. 3. Powell JR, Vozeh S, Hopewell P, et al. Theophylline disposition in acutely ill hospitalized patients. Am Rev Respir Dis. 1978;118:229–238. 4. Chang CK, Lauer BA, Bell TD, et al. Altered theophylline pharmacokinetics during acute respiratory viral illness. Lancet. 1978;1:1132–1133. 5. Renton KW. Theophylline pharmacokinetics in respiratory viral illness. Lancet. 1978;2:160–161.
TL;DR: The case may provide the following important experiences: a case of acute, extremely profound, and life-threatening thrombocytopenia after tirofiban administration without severe bleeding was reported, and the platelet count recovered spontaneously without platelet transfusion.
Abstract: reviews also found that tirofiban-induced thrombocytopenia usually resolved after a mean of 2.1 days and disappeared within a week.6,8 Interestingly, in our case, considering the patient had no history of hemorrhagic disease and the CRUSADE Bleeding Score was 22 scores (very low risk of bleeding) on admission, we did not give a platelet transfusion for the patient. Despite the platelet count vanished at the onset of thrombocytopenia and rose slightly in the first 24 hours, we only observed minor bleeding in the skin, urinary tract, and alimentary tract and recovered 48 hours later. Besides, during the treatment, the antiplatelet drugs were discontinued, and supportive treatment was maintained. Finally, the platelet count exceeded 100 3 109/L on day 7 and without obvious bleeding during this period. In fact, our case may provide the following important experiences: (1) a case of acute, extremely profound, and life-threatening thrombocytopenia after tirofiban administration without severe bleeding was reported; (2) the platelet count recovered spontaneously without platelet transfusion; (3) the tirofiban-induced thrombocytopenia seemed to be easily resolved by the interruption of antiplatelet drugs and early supportive treatment; and (4) the early discovery of tirofiban-induced acute profound thrombocytopenia is very important. Therefore, our report emphasizes the need for routine testing in all patients who were treated with tirofiban.
TL;DR: 1. Naguy A. Psychopharmacotherapy of attentiondeficit/hyperactivity disorder in children with comorbid conditions and two adolescent cases of psychotropic-related nonaffective oniomania.
Abstract: 1. Naguy A. Psychopharmacotherapy of attentiondeficit/hyperactivity disorder in children with comorbid conditions. Pediatr Neurol. 2018;82:7–12. 2. Ghanizadeh A. Methylphenidate-associated enuresis in attention deficit hyperactivity disorder. J Pediatr Neurol. 2008;4:306–307. 3. Tang CS, Chou WJ, Cheng ATA. Osmotic release oral system (oros) methylphenidate-induced double incontinence: a case report. Prim Care Companion J Clin Psychiatry. 2010;12:PCC.09l00870. 4. Heinrich TW. A case report of methylphenidate-induced dyskinesia. Prim Care Companion J Clin Psychiatry. 2002;4: 158–159. 5. Balazs J, Besnyo M, Gadoros J. Methylphenidate-induced orofacial and extremity dyskinesia. J Child Adolesc Psychopharmacol. 2007;17:378–381. 6. Narine C, Sarwar SR, Rais TB. Adderall-induced trichotillomania: a case report. Innov Clin Neurosci. 2013;10: 13–14. 7. Naguy A, Abdelhakim W, Al-Tajali A. Two adolescent cases of psychotropic-related nonaffective oniomania. J Child Adolesc Psychopharmacol. 2018;28: 295–296.
TL;DR: The family meeting is an increasingly important component of a patient's care plan for those living longer and with complex medical conditions and therefore, should be viewed as a medical intervention.
Abstract: Background: Acute care hospitals provide care for older adults who have complex medical needs and fluctuating caregiving demands. Often one's ability to live independently can be threatened when faced with an acute illness in a hospital setting. It is in this acute care setting that the family meeting is most needed and recommended for treatment planning. Areas of Uncertainty: Meetings are often needed to establish care plans. However, there are challenges to holding family meetings. Some families are unable or unwilling to participate and there may be limited availability of space and time to conduct an adequate family meeting. These can contribute to delays in decision making. Therapeutic Advances: A family meeting is, therefore, a form of therapeutic intervention to be used during a patient's hospital stay. This article highlights the importance of family meetings as a means of medical intervention; describing the purpose, challenges, and education on carrying out the intervention. The primary reason for a family meeting is to facilitate communication between the health care team, decision makers, and caregivers. Participants should prepare ahead and a successful family meeting should follow a structured format to help minimize barriers and maximize therapeutic goals, including why the meeting is being called, who will participate, and when/where it will be held. A structured format allows for information to be shared from care provider to patient/family, including diagnosis, prognosis, therapy, and discharge plans and needs. At the end of the meeting, a summary should be provided. Conclusions: The population is aging and therefore these meetings need to become more common. The family meeting is an increasingly important component of a patient's care plan for those living longer and with complex medical conditions. Family meetings have shown improved outcomes and patient satisfaction, and therefore, should be viewed as a medical intervention.
TL;DR: A 15-year-old Kuwaiti youngster, a known case of autism spectrum disorder (ASD), intellectual disability, and epilepsy, attending special schooling, was escorted by his parents for escalating behavioral dyscontrol, notably irritability, fitful sleep, and socially flouting oversexualized behaviors.
Abstract: To the Editor: A 15-year-old Kuwaiti youngster, a known case of autism spectrum disorder (ASD), intellectual disability, and epilepsy, attending special schooling, maintained on valproate for seizure control, was escorted by his parents for escalating behavioral dyscontrol, notably irritability, fitful sleep, and socially flouting oversexualized behaviors. Medical and environmental causation of this behavioral decompensation was meticulously ruled out. He could not tolerate a trial on risperidone where he developed recurrent extrapyramidal side effects. He failed a 6-week trial on 15 mg/d aripiprazole. Clonidine was also tried but prematurely aborted for severe hypotension and symptomatic bradycardia. We suggested a trial with mirtazapine, as data from the literature support its use for sexually inappropriate behaviors in ASD, and also to help with sleep and irritability. We went to 45 mg/d over 4 weeks. Sleep improved markedly, irritability diminished significantly, and most importantly, sexual behaviors were greatly tamed. Both frequency and severity of aggression became obviously less. This was well sustained at follow-ups week 4, 8, and 12. ASD, especially the low-functioning, is typically coupled with a multitude of challenging behaviors that might interfere with acquisition of more functional and adaptive behaviors, add to caregiver distress, and, are primarily cause of referral to child psychiatrists. One of these problem behaviors that emerge with transition into adolescence is the inappropriate sexual behaviors (ISBs) in up to 30% of cases, in tandem with hormonal surge, which is often difficult to accommodate and surprisingly less well studied in literature.1 These behaviors include, inter alia, masturbation (onanism) in public, disrobing, inappropriate touching, copropraxia (obscene gestures), pornographomania. This is further compounded in this population by deficits in social communication and theory of mind, which lie at the core of ASD with executive dysfunction and poor social judgement rendering psycho-education of “sexuality” difficult to contemplate. Moreover, in conservative and religious communities, like ours, talking openly about these issues remains a “taboo.” In ASD population, ISBs might subserve self-soothing or self-stimming (sensory) functions that tend to maintain these maladaptive behaviors. It might then turn part of routine. Although these behaviors can be seen normative in neurotypicals, in ASD population, it might prove seriously risky. Lack of education, using inappropriate “fetish,” too excessive masturbation, self-injury during the act, indecent exposure, associated aggression, and forensic repercussions. all can accentuate ramifications of ISBs in ASD and call for action. Working differential for oversexualized behaviors in ASD should entail sexual abuse (heightened vulnerability), drug-induced impulse dyscontrol (eg, aripiprazole with partial D2 agonism),2 communication vehicle (albeit ineffective), superimposed bipolarity, imitating behaviors (exposure to nudity in the vicinity). When parents opt to go for medications, when it goes out of control, which is usually the case, only few pharmacological choices are available and unfortunately with only flimsy evidence base that might be ascribed to the complex nature of these behaviors and factors at play. Apart from the ethical dilemma surrounding the topic, these options include the atypical antipsychotic, risperidone by virtue of potent D2 blockade in the tuberoinfundibular pathway can result in hyperprolactinemia and ergo decreasing sexual drive. Herguner et al3 have reported the effectiveness of risperidone–paroxetine combination for ISBs in an adolescent with ASD/intellectual disability. Selective serotonin reuptake inhibitors might be used similarly, especially if these ISBs have a compulsive flavor or part of restricted and repetitive behaviours.4 Agonistic actions at 5HT2A might be contributory. In the same vein, Ayaydin and Ulgar5 have reported on an interesting case of an autistic 30-month-old girl with global developmental delay that favorably responded to escitalopram 1.5 mg/d for early childhood masturbation. The NaSSA antidepressant, mirtazapine, has been proven effective for ISBs in case series of 9 subjects with ASD by Coskun et al.6 Other case reports again by Coskun and Mukaddes,7 by Albertini et al,8 and also by Nguyen and Murphy9 have attested to the efficacy of mirtazapine for ISBs in ASD due to antilibidinal properties. The b-blocker, propranolol, at a low dose (10 mg bid) has been reported by Deepmala and Agrawal10 to help with ISBs in an adolescent with ASD. Mechanisms include reduction in central sympathetic outflow, impaired vasodilatation of corpora cavernosa, Letters to the Editor e751
TL;DR: Cefepime-Induced Neurotoxicity: An Underappreciated Cause of Encephalopathy Ankita Subedi;Swachchhanda Songmen;Venkanta Manchala;Joseph Mattana; American Journal of Therapeutics.
Abstract: Cefepime-Induced Neurotoxicity: An Underappreciated Cause of Encephalopathy Ankita Subedi;Swachchhanda Songmen;Venkanta Manchala;Joseph Mattana; American Journal of Therapeutics
TL;DR: A 39-year-old woman with a history of hyperthyroidism who developed fast atrial fibrillation secondary to thyrotoxic storm and after the initiation of intravenous diltiazem drip develops hypotension, bradycardia, then asystole cardiac arrest.
Abstract: Clinical features The patient we present is a 39-year-old woman with a history of hyperthyroidism who developed fast atrial fibrillation secondary to thyrotoxic storm. After the initiation of intravenous diltiazem drip, she developed hypotension, bradycardia, then asystole cardiac arrest. Therapeutic challenge It is well known that calcium channel blockers and beta blockers should be used with extreme caution if the patient with thyroid storm has decompensated heart failure with reduced ejection fraction. Despite this, it is recognized that guidelines for the management of thyroid storm do not include an algorithm of action in this situation. Thus, dealing with low-output failure during thyroid storm may pose a critical challenge. Solution A significant portion of patients with thyrotoxic storm have an underlying low-output cardiac failure. Early identification, proper hemodynamic monitoring, and administration of the agents with appropriate pharmacodynamic profile and therapeutic potentials are essential to avoid treatment-induced cardiogenic shock.
TL;DR: Elderly patients are more sensitive to centrally acting medications and often require lower doses than younger patients because of alterations in pharmacokinetics, and a newer medication, dexmedetomidine, has demonstrated some benefit over other sedatives and may have a role in the management of delirium.
Abstract: Older adults currently account for over half of all intensive care unit admissions. Although advances in critical care medicine have led to improved survival, critical illness is still associated with high short-term and long-term morbidity and mortality.
Elderly survivors of critical illness often have long-lasting physical, cognitive, and psychological disabilities. Several iatrogenic risk factors for post-critical illness impairments have been identified, including delirium, deep sedation, and inadequate analgesia. Multicomponent interventions or bundles, which target many of these risk factors, have been shown to improve patient outcomes. However, there is limited literature that addresses the optimal pharmacologic management of analgesia and sedation in elderly critically ill patients who are known to have altered pharmacokinetics and pharmacodynamics. There are also uncertainties regarding the treatment and prophylaxis of delirium in this patient population.
Various interventions can improve the pharmacologic management of pain, agitation, and delirium and subsequently improve outcomes in critically ill elderly patients. Pain should be managed with multimodal therapy and opioids should be used judiciously. Benzodiazepines should be avoided and dexmedetomidine may be the best first-line sedative in this population. Only patients with hyperactive delirium should receive treatment with antipsychotics and there is likely no role of antipsychotics for delirium prophylaxis. New literature suggests that dexmedetomidine may be effective for the prevention and treatment of intensive care unit delirium.
Elderly patients are more sensitive to centrally acting medications and often require lower doses than younger patients because of alterations in pharmacokinetics. A newer medication, dexmedetomidine, has demonstrated some benefit over other sedatives and may have a role in the management of delirium. Overall, more research is needed on the pharmacologic management of pain, sedation, and delirium in the elderly critically ill population.
TL;DR: Complicated and upper urinary tract infections require broader empiric coverage and measures should be taken to de-escalate treatment as early as possible, given the increasing prevalence of multidrug-resistant organisms.
Abstract: Background: Urinary tract infection treatment can be difficult in the geriatric population. These patients often require a more nuanced approach due to recurrent, resistant, and catheter-associated infections. Areas of Uncertainty: Although some attempts have been made to prevent urinary tract infections using cranberry products, probiotics, and nonpharmacologic means, current interest lies largely with the development of new antibiotics to treat increasingly resistant organisms. Therapeutic Advances: Efforts to reduce the development of resistance starts with judicious and appropriate empiric use of antibiotics. Fluoroquinolones are no longer recommended as first-line therapy due to adverse reactions and the development of resistance. Complicated and upper urinary tract infections require broader empiric coverage and measures should be taken to de-escalate treatment as early as possible. Antimicrobial stewardship programs are recommended to aid in these efforts in addition to antibiotic selection in the presence of multidrug-resistant organisms such as those producing extended spectrum beta-lactamase or carbapenemase. Multidrug-resistant organisms are often present in catheter-associated urinary tract infections so broad empiric coverage should be initially started. Catheter-associated urinary tract infections should generally be treated for 7–14 days depending on the rate of clinical improvement, and fungal coverage is often also necessary. Ceftolozane/tazobactam, ceftazidime/avibactam, and meropenem/vaborbactam were recently approved in the US for treating multidrug-resistant organisms and several more agents are in development, such as parenteral fosfomycin. Ceftolozane/tazobactam is effective for treating Pseudomonas aeruginosa and other gram-negative organisms, even those that produce extended spectrum beta-lactamases. Ceftazidime/avibactam is effective solely for gram-negative organisms, including those that produce various carbapenemases, but efficacy for P. aeruginosa is variable. Both combinations are approved for complicated urinary tract infections in addition to complicated intra-abdominal infections. Several medications are currently in the pipeline to treat multidrug-resistant organisms. Meropenem/vaborbactam was approved for complicated urinary tract infections and its coverage includes carbapenem-resistant Enterobacteriaceae. Fosfomycin, currently available orally and first line for uncomplicated urinary tract infections, is being evaluated for intravenous use for methicillin-resistant Staphylococcus, vancomycin-resistant Enterococcus, and gram-negative bacilli that produce both extended spectrum beta-lactamase and carbapenemase. Conclusions: Urinary Tract Infections are a common cause of hospitalization in older adults. Antibiotic selection and antimicrobial stewardship programs are important given the increasing prevalence of multidrug-resistant organisms.