1. Ampicillin/sulbactam 3 gm every 6 hrs
   
2. Ceftriaxone 1gm every 24 hrs
   
3. Piperacillin/tazobactam 4.5 every 8 hrs (extended infusion)
   
4. Cefepime 2 gm every 12 hrs
   
5. Meropenem 1 gm every 8 hrs

ESBLs are plasmid‐mediated enzymes that inactivate all β‐lactam antibiotics including penicillins, third‐ and fourth‐generation cephalosporins (ceftriaxone and cefepime, respectively), and monobactams. Carbapenems and cephamycin are effective against ESBLs. Detection of ESBLs is often difficult and some microbiology laboratories do not employ reliable methods, which may result in false susceptible reporting of ESBL strains to cefotaxime, ceftazidime, and ceftriaxone. Cefepime, a fourth‐generation cephalosporin, does not appear to induce this type of chromosomal‐mediated resistance to the same degree as ceftazidime, but is susceptible to the action of ESBLs. Most ESBLs also co‐express resistance to other agents including aminoglycosides and fluoroquinolones. Carbapenems (specifically meropenem) are the most effective agents against ESBLs. An ESBL E‐test should be performed for this isolate, and the patient should be started on meropenem.

Answer: E

Ghafourian S, Sadeghifard N, Soheili S, et al. Extended spectrum Beta‐lactamases: definition, classification and epidemiology. Curr Issues Mol Biol. 2015; 17 :11–21. Epub 2014 May 12.

Nathisuwan S, Burgess DS, Lewis JS . Extended‐spectrum beta‐lactamases: epidemiology, detection, and treatment. Pharmacotherapy. 2001; 21 (8):920–928. PMID: 11718498

McDaniel J, Schweizer M, Crabb V, et al. Incidence of Extended‐Spectrum β‐Lactamase (ESBL)‐ producing Escherichia coli and Klebsiella Infections in the United States: a systematic literature review. Infect Control Hosp Epidemiol. 2017; 38 (10):1209–1215. PMID: 28758612

Which one of the following analgesics for postoperative pain management is the best choice for this patient?

1. Primarily renally cleared.
   
2. Cheaper cost compared to vecuronium.
   
3. Is an aminosteroid‐based neuromuscular blocking agent, similar to rocuronium.
   
4. Associated with better outcomes in acute respiratory distress and traumatic brain injury.
   
5. Fast onset of action and used for emergency airway management.

Cisatracurium is a widely used nondepolarizing neuromuscular blocking agent (NMBA). Cisatracurium, an isomer of atracurium, undergoes spontaneous chemical degradation (not an enzymatic process) in a process known as Hofmann elimination. The cost of cisatracurium is substantially higher compared to other NMBA. Other NMBAs like pancuronium, rocuronium, and vecuronium are aminosteroid based and their elimination can be affected by hepatic or renal dysfunction. There are three randomized trials that have shown improvement with oxygenation in ARDS patients using cisatracurium. Two additional randomized trials found no decrease in intracranial pressure, mean arterial pressure, cerebral perfusion pressure, or cerebral blood flow velocity with cisatracurium. With atracurium, these parameters decreased and a subsequent rebound in elevated intracranial pressure was noted. Cisatracurium has a relatively slow onset, and should not be used for emergency airway management. Cisatracurium is often the paralytic of choice in patients with severe hepatic and renal dysfunction. Hofmann elimination is a temperature‐ and pH‐dependent process, and therefore the rate of degradation is highly influenced by body pH and temperature; an increase in body pH favors the elimination process, whereas a decrease in temperature slows down the process.

Answer: D

Szakmany T, Minerva WT . Use of cisatracurium in critical care: a review of the literature. Anestesiol. 2015; 81 (4):450–60. Epub 2014 Apr 10.

Sparr HJ, Beaufort TM, Fuchs‐Buder T . Newer neuromuscular blocking agents: how they compare with established agents? Drugs. 2001; 61 :919–942.

1. Alprazolam withdrawal is typically less severe compared to other benzodiazepines.
   
2. Due to the long half‐life, the abuse potential is lower compared to other benzodiazepines.
   
3. Alprazolam has a slow absorption and high lipophilicity.
   
4. Alprazolam uniquely affects dopaminergic function in the brain.
   
5. Rebound anxiety is more commonly seen with diazepam withdrawal than with alprazolam withdrawal.

Alprazolam has a high misuse potential and more severe withdrawal symptoms compared to other benzodiazepines. Alprazolam has unique pharmacokinetic properties since it is less protein‐bound compared to other benzodiazepines resulting in rapid absorption, low lipophilicity, and short half‐life. The half‐life for alprazolam is 8–16 hours, while the half‐life of diazepam is 22–72 hours (assuming healthy adult). In addition, alprazolam does not accumulate oxidative metabolites. Diazepam and its metabolites accumulate in the body and after discontinuation, there is a slow washout leading to less severe withdrawal symptoms. Alprazolam also crosses the blood‐brain barrier and affects the dopaminergic function in the striatum leading to increased serotonin levels, thus, making it higher risk for abuse and misuse. Alprazolam withdrawal is more complicated and has a unique rebound anxiety associated with it.

Answer: D

Ait‐Daoud N, Hamby AS, Sharma S, et al. A review of alprazolam use, misuse, and withdrawal. J Addict Med. 2018; 12 (1):4–10.

1. It works on GABA receptors, like propofol.
   
2. Side effects are mostly hemodynamic alterations such as hypotension, bradycardia, and hypertension.
   
3. It is mainly eliminated via the kidneys and abnormal renal function can affect elimination.
   
4. It has a long half‐life, usually about 12 hours in healthy adults.
   
5. In the ICU, it can be used for deep sedation and with paralytics.

Dexmedetomidine is a selective α₂ adrenoceptor agonist that is used for its anxiolytic, sedative, and analgesic properties. Propofol and benzodiazepines both act on GABA receptors (Answer A). The side effects of dexmedetomidine are mainly hemodynamic changes, to include hypotension, sometimes hypertension, and bradycardia (Answer B). It is mainly hepatically eliminated and elimination can be impacted by hypoalbuminemia and liver failure. The half‐life of dexmedetomidine is 2–3 hours in healthy adults and 2.2–3.7 hours in ICU patients (Answer D). It is approved for light to moderate sedation, not for deep sedation. It should not be used with paralytics in the ICU as it does not provide adequate sedation and cannot achieve the Richmond Agitation Sedation Score (RASS) of ‐4 or ‐5 that is recommended for paralytics (Answer E).

Answer: B

Weerink MAS, Struys MMRF, Hannivoort LN, et al. Clinical pharma‐cokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet. 2017; 56 (8):893–913.

Oddo M, Crippa IA, Mehta S, et al. Optimizing sedation in patients with acute brain injury. Crit Care. 2016; 20 (1):128.

1. Phytonadione 10 mg orally once.
   
2. Four‐factor prothrombin complex concentrate (PCC) 50 units/kg IV infused over 30 min.
   
3. Tranexamic acid 1 gm IV over 10 minutes and followed by 1 gm IV over 8 hours.
   
4. Fresh frozen plasma 15 mL/kg and repeat if INR > 3 on post‐transfusion laboratory.
   
5. Phytonadione 10 mg IV infusion daily for three days.

This patient has an acute gastrointestinal hemorrhage complicated by supratherapeutic warfarin and hemodynamic instability. Reversal should be with four‐factor PCC (Kcentra). Four‐factor PCC contains factors IIa, VIIa, IXa, and Xa; proteins C, S, and Z; antithrombin III; and a small amount of heparin. Because of the heparin in the preparation, a patient with a history of heparin‐induced thrombocytopenia, or an allergy to heparin, should not receive four‐factor PCC (Kcentra). However, patients can receive activated four‐factor PCC (FEIBA). Given his weight and elevated INR (INR > 6), the dose should be 50 units/kg, not to exceed 5000 units. For an INR 2–4, the dose should be 25 units/kg, not to exceed 2500 units; and for INR 4–6, the dose should be 35 units/kg, not to exceed 3500 units. While phytonadione (vitamin K) should be given intravenously (not orally ‐ Answer A), the onset is 6–12 hours, and would not rapidly reverse this patient’s severe supratherapeutic INR. Fresh frozen plasma requires large volumes, often has incomplete INR correction, has a risk of transfusion‐related reactions, and requires extended time to achieve hemostasis, and therefore would not be ideal for a hemodynamically unstable patient. While tranexamic acid, an antifibrinolytic agent, has been shown to be beneficial in trauma and obstetric hemorrhage in studies such as CRASH 2 and WOMAN trial, respectively, it should not be used for warfarin reversal.

Answer: B

Daley, MJ, Bauer, SR. Shock Syndromes II: hypovolemic, critical bleeding, and obstructive. 2019 ACCP Critical Care Pharmacy Preparatory Review and recertification Course. 2019

1. A 46‐year‐old man with hypertension and hyperlipidemia who is scheduled to undergo a laparoscopic colostomy reversal with colorectal anastomosis.
   
2. A 63‐year‐old man with end‐stage renal disease on dialysis and diabetes who is scheduled to undergo a sigmoid resection for cancer.
   
3. A 55‐year‐old woman with chronic back pain who is currently taking 15 mg morphine equivalents daily and is scheduled to have a laparoscopic gastric bypass.
   
4. A 36‐year‐old woman who is postoperative day 4 following a small bowel resection secondary to a small bowel obstruction and has a persistent ileus.
   
5. A 68‐year‐old man with COPD who is postoperative day 3 following a right hemicolectomy for cancer with end ileostomy and is now having 1500 mL/day output from his nasogastric tube.

Alvimopan is a selective peripherally acting μ‐opioid receptor antagonist that specifically targets peripheral μ receptors in the GI tract. It is used to accelerate time to upper and lower gastrointestinal (GI) recovery following large or small bowel resection surgery in patients who undergo a primary anastomosis. Alvimopan blocks the adverse effects of opioids on the GI tract without affecting overall analgesia. It has been shown to reduce time to GI transit and subsequently reduce hospital time. Alvimopan is indicated for planned inpatient surgery in patients undergoing partial bowel resection with primary anastomosis. Ideal dosing is a single 12 mg capsule 30 minutes to 5 hours prior to surgery, and then subsequent twice daily dosing beginning on postoperative day 1, for a maximum of 7 days (15 doses) or until discharge. Patients must remain inpatient while taking alvimopan. Alvimopan is contraindicated in patients who have received therapeutic dosing of opioids for more than 7 days prior to surgery, have severe hepatic impairment, or end‐stage renal disease. It should not be used in patients with a small bowel obstruction or in those patients who will not undergo a primary anastomosis. Patient B is not a candidate due to end‐stage renal disease. Patient C is not a candidate due to chronic high‐dose opioid usage prior to surgery. Patient D is incorrect since she is postoperative from small bowel obstruction with a persistent ileus. Patient E is incorrect because he is postoperative, did not have a primary anastomosis, and is having high‐volume nasogastric tube output.

Answer: A

Curran MP, Robins GW, Scott LJ, et al. Alvimopan. Drugs. 2008; 68 (14):2011–9.

Xu, LL, Zhou XQ, Yi PS, et al. Alvimopan combined with enhanced recovery strategy for managing postoperative ileus after open abdominal surgery: a systematic review and meta‐analysis. J Surg Res. 2016; 203 :211–221.

Vaughan‐Shaw PG, Fecher IC, Harris S, et al. A meta‐analysis of the effectiveness of the opioid receptor antagonist alvimopan in reducing hospital length of stay and time of GI recovery in patients enrolled in a standardized accelerated recovery program after abdominal surgery. Diseases Colon and Rectum. 2012; 55 :611–620.

1. Aggressive fluid resuscitation will not alter the volume of distribution in morbidly obese patients.
   
2. Metabolic clearance by the liver, mostly via the cytochrome P450 system, may be compromised in the critically ill patient by decreases in hepatic blood flow, intracellular oxygen tension, and cofactor availability.
   
3. Gut wall edema, changes in gastric or intestinal blood flow, concurrent administration of enteral nutrition, and incomplete oral medication dissolution has no effect on drug absorption.
   
4. The response to antibiotics that have time‐dependent killing pharmacodynamics would be improved by administering a higher dose of drug to increase the area under the inhibitory curve.
   
5. Deceased in renal function decreases the half‐life of medications cleared via the kidney and result in accumulation of drugs or their metabolites.

Critically ill patients have alterations in medication pharmacokinetics and pharmacodynamics. Pharmacokinetics characterizes what the body does to a drug—the absorption, distribution, metabolism, and elimination of the drug. Pharmacodynamics is what the drug does to the body and describes the relationship between the concentration of drug at the site of action and the clinical response observed. Many factors affect drug absorption, distribution, and clearance in the critically ill patient. Failure to recognize these variations may result in unpredictable serum concentrations that may lead to therapeutic failure or drug toxicity. Drug absorption is altered by gut wall edema and stasis, changes in gastric and intestinal blood flow, concurrent medications and therapies such as enteral nutrition, and incomplete disintegration or dissolution of oral medications (Answer C). The volume of distribution describes the relationship between the amount of drug in the body and concentration in the plasma. Fluid shifts, particularly after fluid resuscitation, and protein binding changes that occur during critical illness, alter drug distribution (Answer A). Plasma protein concentrations may change significantly during critical illness and may affect the volume of distribution by altering the amount of the active unbound or free drug. Metabolic clearance by the liver is the predominant route of drug detoxification and elimination. With hepatic dysfunction that may occur in the critically ill patient, drug clearance may be decreased secondary to reduced hepatic blood flow, decreased hepatocellular enzyme activity, or decreased bile flow. A common pathway for drug metabolism is the cytochrome P₄₅₀

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