Which of the following correctly pairs the pharmacodynamics with the antibacterial agents?
Correct Answer: A
The pharmacodynamics of the antimicrobial agents guide dosing regimen. There are two pharmacodynamic profiles that most antibacterial agents can be classified into (time-dependent and concentrationdependent), which must be considered for optimal efficacy of those agents. Time-dependent agents depend on duration above the minimum inhibitory concentration for optimal bactericidal activity. Here, the frequency of dosing is an important aspect of their antimicrobial effect because a higher frequency of administration will increase the duration of exposure to the drug. Examples of drugs in this category are beta-lactams, macrolides, linezolid, and vancomycin (table below):
On the other hand, antimicrobial effect of concentration-dependent agents depends on the concentration of free drug above the minimum inhibitory concentration. With these agents, increasing the amount or concentration of the drug relative to the minimum inhibitory concentration (or the area under the curve relative to the minimum inhibitory concentration) optimizes antimicrobial efficiency. And decreasing dosing frequency prevents accumulation of the drug and thereby reduces its side effects. Examples of drugs in this category are fluoroquinolones, aminoglycosides, daptomycin (table below):
A 49-year-old male with a past medical history significant for hypertension and end-stage renal disease on hemodialysis is admitted to the ICU in septic shock from pneumonia. He is intubated and mechanically ventilated, and requires vasopressor support. Blood cultures grew multidrug–resistant Acinetobacter baumannii. You begin appropriate treatment. Over the course of several hours you begin to notice increasing vasopressor requirements and increasing peak airway pressures.
Which of the following antimicrobial choices could adequately explain this scenario?
Correct Answer: C
The most likely culprit here is colistin. Colistin is a concentrationdependent bactericidal antibiotic that has both hydrophilic and lipophilic portions, which bind to the anionic lipopolysaccharides on the outer cell membrane of gram-negative bacteria leading to increased permeability of the cellular wall, causing leakage of cell contents, eventually resulting in cellular demise. Colistin has a narrow range of activity, primarily being utilized in the treatment of infections with Pseudomonas aeruginosa and A. baumannii. Colistin does NOT have activity against gram-positive bacteria such as Burkholderia cepacia, Serratia marcescens, Moraxella catarrhalis, Proteus spp., Providencia spp., and Morganella morganii.
Colistin is renally cleared and dose adjustments for IV forms in patients with kidney disease must be considered to avoid, or at least minimize, the potential nephrotoxic effects. Neurotoxicity is also of concern with the IV formulation of colistin. When administered in the aerosol form, up to approximately 10% of patients may develop hypersensitivity reactions, especially pulmonary symptoms such as bronchospasm, which in some cases can be quite severe. Pretreatment with bronchodilators can help assuage the occurrence or severity of this effect.
Polymyxin B is associated with lower rates of nephrotoxicity than colistin and does not need to be dose-adjusted for renal function. Inhaled tobramycin may cause bronchospasm, but IV formulations are less likely to.
A 54-year-old man with a past medical history of cirrhosis is in the ICU 4 days after suffering severe burns to >40% of his body while at work. His respiratory status has been rapidly declining, and he is currently requiring BiPAP; however his P:F ratio is now <200 and his last chest radiograph supports your concern for acute respiratory distress syndrome. You make the decision to intubate and suspect that he will need continuous neuromuscular blockade.
Which of the following neuromuscular blocking drugs will be most appropriate in this patient for intubation and continuous blockade?
Correct Answer: D
When considering neuromuscular blocking agents in the critically ill, the physician must take into account the pathophysiology of the patient, the urgency with which he or she must secure a patient’s airway, whether or not there is a need for continuous administration of a neuromuscular blocking agent, and the effects that agent will have on the patient.
Although succinylcholine is a very popular agent in the facilitation of intubation because of its rapid onset and short duration, its use in the critically ill population is limited for numerous reasons, primarily. Upregulation of extrajunctional nicotinic Ach receptors in this population can lead to a potentially adverse, if not fatal, hyperkalemia. Other contraindications for the use of succinylcholine include patients with or without a family history of malignant hyperthermia, muscular dystrophy, burns >48 hours (risk can be elevated for up to 1 year after the burn), spinal cord injury >24 hours, strokes >72 hours, and patients at risk for exaggerated hyperkalemia (rhabdomyolysis, hyperkalemic patients with ECG changes).
Non-depolarizing agents tend to have better safety profiles in the critically ill population. They do not cause fasciculations because of the competitive antagonism of the end plate. Rocuronium is the most commonly used alternative to succinylcholine for intubation in the critically ill because of its fairly rapid onset (approximately 60 seconds), intermediate duration, and low active metabolite production after metabolism. Rocuronium is excreted mainly through the biliary tract with minimal renal excretion. Thus, rocuronium infusion is not preferred in patients with cirrhosis. Vecuronium has a much longer onset time and has more renal excretion making it a poorer choice in the critically ill.
Cisatracurium and atracurium are other non-depolarizing agents that do not undergo hepatic metabolism, nor do they have hepatic or renal clearance. Atracurium is metabolized through nonspecific plasma esterases and Hoffman elimination. Atracurium can also lead to histamine release, causing flushing, tachycardia, and hypotension, which may make it less suitable in the critically ill. Cisatracurium is metabolized exclusively via Hoffman elimination and is approximately four times as potent as atracurium. Cisatracurium has no active metabolites and does not lead to histamine release and has a faster onset than atracurium, making it a better choice than atracurium in the critically ill.
A 48-year-old, male, liver transplant recipient is readmitted 4 months postsurgery because altered mental status. On examination, he is confused and agitated; the rest of the examination is unremarkable. A review of his medications indicates that he in on lisinopril, prednisone, and tacrolimus. Laboratory tests show:
The results of his complete blood count and the rest of the chemistry profile are normal. CT scan of the brain is normal.
What is the most likely cause of this patient’s current presentation?
Tacrolimus is a calcineurin inhibitor that suppresses the immune system by preventing IL-2 production by T cells and is metabolized via CYP3A4. The adverse effects of the calcineurin inhibitors are primarily nephrotoxicity ranging from minimal to irreversible damage. In addition, tacrolimus may cause neurotoxicity, which can be severe enough to warrant immediate cessation of the medication. The need for frequent and specific monitoring of drug concentrations remains essential because the therapeutic dosing and pharmacokinetics of tacrolimus can demonstrate wide variability among recipients.
Antifungals, such as fluconazole, and multiple classes of antibiotics, such as macrolides, are known inhibitors of of the CYP3A4 system and can lead to increased and toxic blood levels of tacrolimus if not carefully monitored.
Normal-pressure hydrocephalus (NPH) is characterized by pathologically enlarged ventricular size with normal opening pressures on lumbar puncture. It classically presents with cognitive impairment, gait disturbance, and urinary incontinence. Secondary NPH can occur as a consequence of chronic meningitis or ongoing meningitis.
Calcineurin inhibitor toxicity should be part of the differential diagnosis in patients presenting with new renal and neurological toxicity, especially when multiple CYP inhibitors are being used in conjunction with one another.
A 19-year-old female with a past medical history of sensorineural deafness and mitochondrial encephalomyopathy lactic acidosis and strokelike episodes (MELAS) presented to the emergency room with slurred speech, tremor, and unsteady gait. Her physical examination revealed nystagmus, dysarthria, gait and limb ataxia. While in the ER, she had a generalized tonic-clonic seizure for which she was intubated. Phenytoin was also administered and an MRI was obtained that showed bilateral occipitotemporal lesions. She was transferred to the ICU. Phenytoin is discontinued and sodium valproate started. Laboratory results are unremarkable except for elevated lactate levels. EEG confirms seizure activity.
Which of the following is most appropriate next step in management?
Correct Answer: B
The syndrome of MELAS is one of a complex group of heterogeneous multisystem disorders affecting the nervous system, which is maternally inherited and caused by mutations of mitochondrial DNA. Approximately 80% of MELAS cases are associated with an m.3243A>G mutation. Typical presenting symptoms include recurrent strokelike episodes resulting in hemiparesis, hemianopia, cortical blindness, generalized seizure activity, recurrent migraine headaches, short stature, hearing loss, muscle weakness, and cardiomyopathy. MELAS usually presents in patients <40 years of age (though there have been described cases of onset after 40) with encephalopathy, lactic acidemia, and the presence of red fibers from skeletal muscle biopsy. MRI findings will reveal lesions that do not follow vascular territories with diffusion patterns that may be enhanced or mixed. Signal changes will not be static and may show faster resolution than what would be expected in true strokes.
Medications that affect mitochondrial function should be strictly avoided in patients with suspected MELAS. The underlying mechanism to the toxicity of valproic acid in these patients is its interference with and depression of mitochondrial beta oxidation of fatty acids and inhibition of oxidative phosphorylation, which can exacerbate underlying mitochondrial cytopathy.
Although elevated lactate and seizures can occur in sepsis, it is less likely based on her history and imaging. So antibiotics and fluid resuscitation will not be the first next step. Also, tPA is not indicated as MRI findings are not suggestive of acute ischemic stroke.
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