Top Ten Drugs or Classes in the Intensive Care Unit

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Top Ten Drugs (or Classes) in the Intensive Care
Unit

• Rob MacLaren, PharmD, FCCM, FCCP
• Associate Professor
• University of Colorado School of Pharmacy

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Objectives
At this lectures conclusion

• Explain the mechanisms of action of agents
  commonly used in the intensive care unit.
• Describe the clinical application of agents
  commonly used in the intensive care unit.
• Develop a dosing regimen and monitoring plan for
  agents commonly used in the intensive care unit.
• Proton pump inhibitors and histamine-2 receptor
  antagonists analgesics, sedatives and
  neuromuscular blocking agents fluids,
  vasopressors, and inotropes ACLS,
  antiarrhythmics, loop diuretics, and
  antihypertensives anticoagulants and
  procoagulants antibiotics and antifungals.

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Case

• 47 yo male admitted to the MICU with CAP / COPD
  exacerbation (PMH of COPD, CAD, and NIDDM).
• Intubated for hypoxia and eventually placed on
  Assist Control, 15/15-18 bpm, 8 mL/kg, 70, and 7
  cm H2O PEEP to maintain PaO2 90 mmHg and O2sat
  80.
• Patient is agitated and restless (not
  autoPEEP).
• Within hours, Bp 60s/20s and HR 120s.
  Received 4L NS with minimal response.
• What ICU drugs does this patient require and why?

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Proton Pump Inhibitors / Histamine-2 Receptor
Antagonists
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Clinical Applications of Proton Pump Inhibitors /
Histamine-2 Receptor Antagonists

• PPIs
• Treatment of nonvariceal upper gastrointestinal
  hemorrhage
• Esomeprazole, pantoprazole, omeprazole _at_ 80 mg iv
  bolus then 8 mg/hour x 72hrs then 40 mg po/iv
  q12hrs.
• Lansoprazole _at_ 60 mg iv bolus then 6 mg/hour x
  72hrs then 30 mg po/iv q12hrs.
• Prevention of stress-related mucosal hemorrhage
• Esomeprazole, pantoprazole, omeprazole _at_ 40 mg
  po/iv q24hrs.
• Lansoprazole _at_ 30 mg po/iv q24hrs.
• H2RAs
• Prevention of stress-related mucosal hemorrhage
• Famotidine 20 mg iv q12hrs, ranitidine 50 mg iv
  q8hrs, cimetidine 300 mg iv q6hrs.

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Pharmacologic Targets of Proton Pump Inhibitors /
Histamine-2 Receptor Antagonists
GASTROENTEROLOGY.2000118(2)s9-s31
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Monitoring of PPIs and H2RAs

• PPIs
• Advantages Oral/IV formulations, ease of dosing,
  supporting clinical data for NVUGB SRMD, low
  drug interactions, more pH control.
• Disadvantages Possible associations with
  clostridium difficile infection and pneumonia
  some drug interactions (omeprazole) slightly
  higher cost.
• H2RAs
• Advantages Oral/IV formulations, ease of dosing,
  supporting clinical data for SRMD, inexpensive.
• Disadvantages Possible association with
  pneumonia and thrombocytopenia some drug
  interactions (cimetidine) confusion infusion
  rate dependent bradycardia.

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Analgesia, Sedation, Neuromuscular Blockade
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Clinical Applications of Analgesia, Sedation,
Neuromuscular Blockade

• Analgesia
• To prevent / reduce pain and sedation.
• Opioids used most commonly.
• Sedation
• To reduce anxiety and improve comfort (e.g.
  ventilator support).
• Common agents benzodiazepines (GABA receptor
  agonists), propofol (??? MOA).
• Neuromuscular Blockade
• To facilitate mechanical ventilation (extreme
  nonphysiologic modes).
• Common agents succinylcholine (depolarizing) and
  competitive acetylcholine antagonists
  (nondepolarizing).

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Analgesic Agents
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Monitoring of Analgesia

• Pain control
• Subjective facial expressions, guarding,
  restlessness, anxiety, irritable, sleep
  disturbance.
• Objective diaphoresis, verbal response,
  tachycardia, hypertension, muscle tension,
  dilated pupils, tachypnea, spasm. Pain scores.
• Opiate abstinence/withdrawal syndrome
• Subjective agitation, restlessness,
  irritability, anxiety, insomnia, tremor,
  dysphoria.
• Objective tremor, seizure, tachycardia,
  hypertension, fever, diaphoresis, dilated pupils,
  vomiting. Validated tools in NICU and PICU.
• Prevent by dose weaning, transdermal fentanyl,
  enteral methadone.

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Pain Assessment Behavioral Scale (PABS)
Score 0 no evidence of pain. 1-3 Mild pain.
4-6 moderate pain. 7-10 Severe Pain.
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Sedative Agents
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Monitoring of Sedation

• Level of sedation all agents equally efficacious
  with appropriate monitoring but 62 of ICUs use
  sedation scoring.
• Unique side effects
• Prolonged awakening (benzos).
• Propylene glycol toxicity (anion gap met
  acidosis) and ppt with lorazepam.
• Hypertriglyceridemia, pancreatitis, hypercaloric
  intake, hypotension, preservatives, and possible
  immunomodulation with prop.
• Sedation abstinence/withdrawal syndrome
• Agitation, restlessness, anxiety, insomnia,
  tremor, tachycardia, hypertension, fever.

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Monitoring of Sedation

Riker Sedation-Agitation Scale
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Neuromuscular Blocking Agents

• Depolarizing (succinylcholine)
• Used for procedures (e.g. intubation).
• Dose 1-2 mg/kg iv.
• Contraindicated if hyperkalemia, increased ICP,
  crush/burn injury, bronchoconstriction,
  denervation syndrome.
• Nondepolarizing (competitive antagonists)
• Used for intermittently for procedures,
  intracranial pressure, or shivering and
  continuously to facilitate mechanical ventilation
  (extreme nonphysiologic modes).

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Nondepolarizing NMBs
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Neuromuscular Blockade Monitoring

• Train of Four (TOF)
• Using peripheral nerve stimulation, monitor
  number of twitches of ulnar nerve or facial nerve
  in response to preset amount of current (40
  mAmp).
• Response of 4/4 is lt 75 paralyzed, 3/4 is 75-80
  paralyzed, 2/4 is 80-90 paralyzed, 1/4 is
  90-100 paralyzed, and 0/4 is 90-100 paralyzed.
• Use of TOF reduces drug cost and occurrence of
  neuropathies.
• Ventilator synchrony and / or ? ICP.
• Adverse effects neuropathy (reduced with TOF),
  histamine release (atra gt miva gt rest), vagolytic
  (pan gt vec gt roc gt rest), reduced corneal reflec
  (lacrilube, eye drops), drug interactions to ??
  NMB.

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Fluids, Vasopressors, Inotropes
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Fluid Replacement
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Vasopressors and Inotropes
In Pharmacotherapy A Pathophysiologic Approach
(7th ed). DiPiro JT ed. Chicago, Il
McGraw-Hill. 2008.
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? NO and K-ATP
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Vasopressin

• Acts at vasopressin (V) receptors
• Vascular V1 receptors enhance calcium release
  from sarcoplasmic reticulum to vasoconstrict.
  Greatest vasoconstriction in skin, skeletal
  muscle, fat, pancreas, and thyroid gland.
• Renal V2 receptors enhance fluid retention in
  collecting tubules but vasoconstriction of
  efferent gt afferent increases GFR net effect is
  increase urine output.
• V3 receptors increase ACTH (cortisol) release.
• Dose for sepsis 0.01 0.04 units/min (not to be
  titrated to response as this is replacement
  dosage).
• Reduces the dose of the traditional catecholamine
  vasopressor possibly increases urine production.

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Potential Side Effects
In Pharmacotherapy A Pathophysiologic Approach
(7th ed). DiPiro JT ed. Chicago, Il
McGraw-Hill. 2008.
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ACLS, Antiarrhythmics, Diuretcis, and
Antihypertensives
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ACLS Drugs of Interest

• Vasoapressors
• Epinephrine
• Vasopressin
• Rate Control
• Adenosine
• Atropine

• Anti-arrhythmics
• Amiodarone
• ß blockers
• Diltiazem
• Lidocaine
• Magnesium

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Other Code Cart Medications

• Other
• Albuterol nebs
• Calcium chloride
• Dextrose
• Magnesium
• Nitroglycerin
• Sodium bicarbonate
• Dopamine drip
• Lidocaine drip
• Flumazenil
• Naloxone

• Pulmonary Embolism
• tPA- alteplase
• Anaphylaxis
• Epinephrine
• Antihistamines
• Corticosteroids
• Inhaled ß- agonists

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Vasopressors

• Epinephrine
• 1st line vasopressor in ACLS algorithm
• Indications
• V Fib / V Tach (after shocking)
• PEA
• Asystole
• Dose
• IV / IO Push 1 mg repeated every 3-5 minutes
• Continuous infusion 0.01 to 0.5 mcg / kg / min
• ET route 2 to 2.5 mg diluted in 10 mL NS
• Intracardiac 0.3 to 0.5 mg
• Other
• Incompatible with sodium bicarbonate
• Vasopressin
• Indications
• V Fib / V Tach (after shocking)
• PEA
• Asystole
• Dose

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Atropine in Pulseless Arrest

• Atropine
• Acetylcholine receptor antagonist- reverses
  cholinergic mediated decreases in heart rate
  (vagolytic effect)
• In slow PEA or Asystole only
• Give 1mg q 3-5 minutes (along w/ epinephrine or
  vasopressin)
• Up to maximum dose of 3mg

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Anti-arrhythmics

• Amiodarone
• MOA blocks K, Na, and Ca channels ß- blocker
  
• Indications
• Recurrent pulseless V Fib / V Tach
• Dose 300mg IV push (dilute in 20-30 mL D5W)
• May follow with 150 mg IV push in 3-5 min
• Available as abboject syringe (150mg/3mL)
• Wide QRS complex arrhythmia w/ pulse
• Dose 150mg IV over 10 minutes, may repeat prn
• Continuous infusion 1mg/min x 6 hours, then
  0.5mg/min x 18 hours
• Considerations
• Long half-life hypo- or hyperthyroid, hepatic or
  pulmonary fibrosis, smurf-like skin must
  dilute in nonPVC bag

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Anti-arrhythmics with PULSE

• Diltiazem
• MOA Ca channel blocker
• Inhibits automaticity in SA node
• Inhibits conduction through the AV node
• Arterial vasodilation
• Indications
• Control VENTRICULAR rate in A Fib / Flutter
• May terminate reentrant arrhythmias reentrant
  arrhythmias
• Avoid in A Fib/flutter associated w/
  Wolff-Parkinson-White syndrome
• Do NOT use in wide-complex rhythm
• Dose
• 15 to 20 mg IV / IO push over 2 minutes
• May repeat dose in 15 minutes at 20 to 25 mg over
  2 minutes
• Continuous infusion 5 to 15 mg/hr, titrated to
  appropriate heart rate

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Re-entry Tachyarrhythmia

• Adenosine
• MOA
• Decreases conduction velocity
• Prolongs the refractory period
• Inhibits AV node conduction
• Indications
• Reentry arrhythmia involving AV or sinus node
• Conversion of paroxysmal supraventricular
  tachycardia
• Will NOT convert A fib, A flutter, or V tach
• May help diagnosis of arrhythmia
• Dose
• 6mg given rapidly IV push over 1 to 3 seconds
  followed by 20 mL NS bolus elevate extremity
• 2nd dose may be given in 1 to 2 minutes if
  needed- 12 mg

Results in conversion to sinus rhythm
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Naloxone

• Opioid mu-receptor antagonist
• Dose
• Suspected emergent narcotic OD 0.4-2mg
• If no response then not likely narcotic OD
• May repeat after 2-3 min if needed
• If not emergent (alive) 0.1-0.2mg given in small
  increments to avoid severe pain
• May induce w/d and may be outlasted by opioid

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Flumazenil

• Benzodiazepine binding site antagonist
• Displaces benzodiazepines binding thereby
  reversing clinical effects
• Dose 0.2mg/dose at 60 second intervals
• May repeat with escalating doses (0.5mg)
• If respond then re-sedate, repeat effective dose,
  maximum recommended 3mg in one hour time
• Rarely see additional response at 5mg
• May induce w/d and may be outlasted by benzo

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Blood Pressure Management
Crit Care 200812237. J Neurol 2006253985-99.
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Vasodilators Nitroglycerin
Mechanism primarily a venous dilator, mild
arterial dilator Administration continuous
infusion via infusion pump 5-200
mcg/min Benefits Decrease in PCWP and slight
decrease in MAP and SVR Adverse effects
hypotension, tachycardia, tolerance
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Loop Diuretics
Mechanism decreased Na/water resorption in the
kidney Administration continuous infusion via
infusion pump or intermittent dosing Furosemide
20-80 mg q1-2 hours PRN 10-40
mg/hr Bumetanide 0.25-4 mg/hr Benefits
decrease in PCWP, pulmonary congestion,
preload, and intravascular volume Adverse
effects volume depletion, electrolyte
imbalance, azotemia, contraction alkalosis,
ototoxicity
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Anticoagulants and Procoagulants
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Mechanisms of Anticoagulants
INTRINSIC SYSTEM
EXTRINSIC SYSTEM
(Collagen)
(Tissue Factor)
XII
XIIa
Heparin
Factor III Ca
XI
XIa
Ca
IX
VII
VIIa
IXa PF 3 Ca VIII
Fondaparinux
LMWH
Xa Ca PF 3 V
X
X
APC
XIII
Thrombin
Prothrombin (II)
XIIIa
Fibrin (monomer/ polymer)
Stable Fibrin Polymer
Fibrinolytics
Fibrinogen (I)
DTI
Adapted from Circulation 2007116552.
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Clinical Profiles
Ann Pharamcother 2006401558-71.
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Dosing of Anticoagulants

• DVT pharmacoprophylaxis
• MICU/SICU UFH 5000 U sc q8hrs.
• Trauma LMWH gt 3400 IU sc q24hrs.
• Ortho LMWH gt 3400 IU sc q24hrs or fondaparinox
  2.5 mg sc q24hrs.
• Burn or Neurosurg UFH 5000 U sc q8hrs or LMWH gt
  3400 IU sc q24hrs IPC/GCS.
• Anticoagulation
• Therapeutic heparin infusion (aPTT).
• High dose LMWH.
• HIT
• DTIs (argatroban, bivalirudin, lepirudin).
• Doses needed usually much lower than recommended.
  

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Blood Products
Pharmacotherapy 20072757S. Pharmacotherapy2007
2769S.
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Pharmacologic Agents
NEJM 20073562301. Pharmacotherapy 20072793S.
Pharmacotherapy20072769S.
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Antibiotics and Antifungals
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Common ICU Antibiotics

• ß-lactams
• Penicillins
• Cephalosporins
• Carbapenems
• Monobactams
• Fluoroquinolones
• Levofloxacin, ciprofloxacin, moxifloxacin,
  gemifloxacin, gatifloxacin
• Aminoglycosides
• Gentamicin, tobramycin, amikacin
• Macrolides
• Erythromycin, azithromycin, clarithromycin
• Others
• Vancomycin, linezolid, daptomycin

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Antibiotics Mechanisms of Action

• ß-Lactam antibiotics
• Inhibit cell wall (peptidoglycan) synthesis
• Fluoroquinolones
• Induce negative supercoils in bacterial DNA by
  inhibiting DNA gyrase.
• Aminoglycosides
• Disrupt protein synthesis through selectively and
  specifically binding to 30S ribosomal subunit.
• Macrolides
• Reversibly bind to the 50S ribosomal subunit to
  inhibits protein translation.
• Others
• Vancomycin inhibits cell wall (peptidoglycan)
  synthesis by high-affinity binding to cell wall
  precursor called D-alanyl-D-alanine.
• Linezolid inhibits an early step in bacterial
  protein synthesis by preventing the formation of
  the tRNAfMet-mRNA-30S (or 50S) subunit ternary
  complex.
• Daptomycin binds to Gram-positive bacterial cell
  membrane by inserting calcium-dependent lipid
  tail and rapidly depolarizes the cell membrane.

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ß-Lactams Adverse Effects

• Relatively low toxicity, generally well tolerated
  especially in low-moderate doses
• Gastrointestinal nausea, vomiting, abdominal
  pain, diarrhea (20-30 incidence with ampicillin)
• Skin rash ? most commonly reported with
  ampicillin and amoxicillin (5-10 vs. 1-2 with
  other penicillins)
• Rash during ampicillin administration does NOT
  necessarily signify a serious hypersensitivity
  reaction
• Hematologic neutropenia, prolonged bleeding
  times, thrombocytopenia
• CNS mental status changes, seizures in high-risk
  patients
• Electrolytes hypokalemia, hypernatremia
• Hepatic transaminase elevations, biliary
  sludging
• Renal interstitial nephritis, acute tubular
  necrosis
• Hypersensitivity (1-10 anaphylactic reactions
  in 0.015 cross-sensitivity 5-10)

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Fluoroquinolones Adverse Effects

• Among the safest and best tolerated of all
  antibiotic classes
• GI nausea, vomiting, diarrhea (1-6)
• CNS headache, dizziness, insomnia (1-6)
• Rash lt1 for most agents, 3-4 for gemifloxacin
• Incidence of rash with gemifloxacin substantially
  higher in women lt40 years of age (10 by 7 days
  of therapy, 15 by 10 days)
• Increased liver transaminases (lt2)
• Glucose abnormalities uncommon, but probably
  increased with gatifloxacin
• Risk factors include renal dysfunction, elderly,
  Type I or II diabetics
• QTc prolongation, risk of cardiac arrhythmias
  low risk overall but possibly higher with
  moxifloxacin
• Risk factors include previous cardiac disease,
  concomitant antiarrhythmic drugs, renal
  dysfunction, electrolyte abnormalities
• Tendonitis or tendon rupture (rare)
• Very low risk of photosensitivity

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Aminoglycosides Adverse Effects

• Nephrotoxicity (usually reversible)
• 8-26 of all patients receiving aminoglycosides
  develop nephrotoxicity
• Aminoglycosides eliminated via glomerular
  filtration
• At high doses and over prolonged periods of time,
  drug accumulates within the proximal tubule cells
  and results in cellular necrosis
• Major risk factors dose and serum levels,
  duration of administration,
  underlying renal disease/injury
• Ototoxicity
• Hearing loss
• High frequency tones usually most effected
• Can result in complete and permanent hearing loss
  
• Vestibular impairment
• Disequilibrium, vertigo, nausea
• Incidence and severity of ototoxicity is time-
  and agent-dependent
• Not always reversible
• Neuromuscular weakness
• Aminoglycosides enhance acetylcholinesterase.
• Skin rashes and drug fever are other adverse
  effects, but considered minor

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Macrolides Adverse Effects

• GI irritability due to the motility-stimulating
  effects
• Thrombophlebitis with IV products
• avoided with adequate dilution (250 ml) and slow
  infusion (45-60 min)
• Allergic reactions skin rash, fever,
  eosinophilia
• Cholestatic hepatitis estolate preparation
  chiefly in adults, pregnant women
• Ototoxicity with high doses, reversible
• Torsade de pointes - rare
• Superinfections - Candida spp.
• Pseudomembranous colitis - rare

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Vancomycin Adverse Effects

• Infusion-related reactions
• Red man or Red neck syndrome (pruritus,
  flushing, rash of upper body) occurs 0-35,
  usually 10-20 minutes after start of infusion
• Nephrotoxicity
• Incidence lt5 when administered alone but
  increased by concomitant use of aminoglycosides
  or other nephrotoxic drugs
• Recent data also suggest daily doses ?4 grams may
  increase risk
• Ototoxicity
• Very unusual
• Tinnitis, vertigo, hearing loss
• Neutropenia, thrombocytopenia (rare)
• Phlebitis and pain at IV administration site
  (common)

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Linezolid Adverse Effects

• Considered to be a safe, well tolerated drug in
  most patients
• GI nausea, vomiting, diarrhea (3-6)
• Headache (2-4)
• Elevation of hepatic transaminases (3-7)
• Reversible bone marrow suppression (1-5)
• Thrombocytopenia, leukopenia, anemia
• Usually occurs late in therapy (gt10-14 days)
• Most common in severely ill patients
• Taste alterations, tongue discoloration (2-3)
• Injection site reactions

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Daptomycin Adverse Effects

• Considered to be a safe, well tolerated drug
• GI constipation, nausea, vomiting, diarrhea
  (3-6)
• CNS Headache, insomnia, dizziness (2-5)
• Rash (4)
• Elevations in creatine phosphokinase (CPK)
• Occurs in lt3 of patients, usually asymptomatic
• Muscle weakness, myalgias observed in early
  studies
• Elevation of hepatic transaminases (3)
• Injection site reactions
• Pneumonia failure

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UCH Anaerobes
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Antifungals Mechanisms of Action
Cell wall Echinocandins (caspofungin,
anidulofungin, micafungin) Inhibit ß-(1-3)
glucan synthase
Plasma membrane
DNA synthesis Flucytosine
Polyenes (amphoterecin) Bind to ergosterol
Azoles (fluconazole, voriconazole, posaconazole)
Inhibit ergosterol synthesis
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Antifungals Clinical Applications
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Other Common Agents

• Corticosteroids (methylprednisolone, prednisone,
  hydrocortisone, dexamethasone)
• Bronchodilators (albuterol, ipratropium)
• Octreotide
• Prokinetic agents (erythromycin, metoclopramide),
  laxatives
• Nutrition
• Electrolytes

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Lifes a Beach but
Ill Take Questions