Pharmacology Flashcards

1
Q

Applications of benzodiazepines in critically ill

A

Sedation
Anxiolysis
Anticonvulsant
Muscle relaxant
Appetite stimulant
Minor cardiovascular and respiratory effects
Used as part of an anesthetic induction protocol for balanced anesthesia
They do NOT provide analgesia

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2
Q

Are benzodiazepines scheduled substances?

A

Yes, class IV

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3
Q

MOA of benzodiazepines

A
  • Act primarily via the inhibitory neutrotransmitter GABA - bind to stereospecific receptors that facilitate the inhibitory actions of GABA
  • May also involve antagonism of serotonin and diminished release or turnover of Ach in the CNS
  • They act at the limbic, thalamic and hypothalamic levels of the CNS
  • Metabolized in the liver to active metabolites, then after conjugation, excreted in urine
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4
Q

Diazepam vs midazolam - differences

A

Diazepam:

  • Not water soluble - formulated in 40% propylene glycol and 10% alcohol vehicle.
  • Propylene glycol - irritant to blood vessels -> causes phlebitis and thrombosis after repeated administration through peripheral vein -> give as CRI or through central line.
  • Prolonged admin of diazepam -> propylene glycol toxicity -> metabolic acidosis, hyperosmolality, neurologic abnormalities and organ dysfunction. Important in CATS.
  • Absorbs to plastic - infusion lines require pre-coating.
  • Both midazolam and diazepam should be protected from light

Midazolam:

  • Water soluble
  • Well absorbed after IM injection.
  • Poorly available when given IR.
  • Can be given as CRI through peripheral vein.
  • JVIM 2018 - intranasal midazolam terminated status epilepticus in 70% of cases compared to rectal diazepam, 20% of cases. All dogs showed sedation and ataxia.
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5
Q

Does benzodiazepines have always sedative effects?

A

No.
Some animals might demonstrate excitation, irritability and depression.
Patients already obtunded most likely will be sedated, especially if combined with an opioid.
Healthier dogs and cats may demonstrate dysphoria, especially if given as solo agent.

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6
Q

Complication of oral diazepam in cats

A

Idiosyncratic reaction - fulminant hepatic failure - acute hepatic necrosis.
Not reported with other routes of administration.

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7
Q

Which one is shorter acting, diazepam or midazolam

A

Midazolam - short elimination Half-life and duration of action - more suitable for CRI than diazepam

Half-life of diazepam - 3 to 6 h

Half-life of midazolam - 1h

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8
Q

How can we reverse benzodiazepines?

A

Flumazenil - antagonist
Sarmazenil - inverse agonist

Marked excitement and dysphoria can be precipitated by either drug.
Significant adverse effects like seizures and acute benzodiazepine withdrawal have been reported

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9
Q

Indications for flumazenil
Doses

A
  • Due to the severe adverse effects, even in cases of benzodiazepines overdose, toxic effects can be managed with supportive care.
  • Rarely indicated in stable patients.
  • Used in critically ill patients with cardiovascular or pulmonary instability.
  • 0.01 to 0.02 mg/kg IV.
  • If requiring frequent dosing - CRI at 0.005 to 0.02 mg/kg/h
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10
Q

Benzos as anticonvulsant therapy
Doses for sedation / anticonvulsant

A
  • Diazepam IM not recommended - IR route preferred
  • Intranasal midazolam preferred over IR diazepam (JVIM 2018)
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11
Q

Benzodiazepines and appetite stimulant

A
  • Low doses benzodiazepines can stimulate appetite, specially in cats
  • MOA - involves binding to benzodiazepine receptors and appears to increase attraction to tastes.
  • Increases both amount of food and rate of consumption.
  • Diazepam at 0.005 to 0.4mg/kg IV q24h or 1mg orally q24h (risk of hepatic toxicity in cats)
  • Food should be readily available - they might begin to eat within a few seconds of administration.
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12
Q

Hepatic encephalopathy and benzos

A
  • Human patients with HE show arousal after flumazenil - suspected increased endogenous benzodiazepines agonist activity.
  • Lack of arousal in other species including dogs and cats.
  • Administration of inverse agonist sarmazenil in research models of acute and chronic HE - improvement of encephalopathies signs - consistent with an increased GABAergic constitutive activity in HE rather than an increase in endogenous benzodiazepine agonist ligands.
  • Sarmanezil should not be considered part of the therapy of HE.
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13
Q

Percentage of cases reporting to veterinary referral centers involving epilepsy

A

0.6% to 2.3%

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14
Q

Age of idiopathic epilepsy

A

1 to 5 years old, but onset has been reported in both older and younger dogs.

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15
Q

Idiopathic epilepsy incidence

A

Higher in dogs, whereas in cats reactive (metabolic or toxic disturbance) and symptomatic (underlying intracranial dz) are more common than idiopathic epilepsy.

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16
Q

Most common anticonvulsants

A

Phenobarbital
Bromide (potassium bromide, sodium bromide)
Zonisamide
Levetiracetam
Felbamate - not used very commonly

Benzodiazepines (diazepam, midazolam, lorazepam, clorazepate) - short life and development of tolerance - used only in emergency treatment.

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17
Q

Phenobarbital MOA and metabolism

A
  • Facilitates GABA-ergic activity - prolongs opening of Cl- channels
  • Believed to inhibit glutamate receptors and voltage-gated calcium channels
  • High bioavailability after PO admin - 86% - 96% - absorbed in 2h, maximal concentration in 4-8h when given PO
  • Protein bound - 45%
  • Metabolized in the liver primary by CYP450 - potent inducer of CYP450 → induces its own metabolism and that of other drugs (benzos, levetiracetam, zonisamide)
  • Medications that inhibit CYP450 → may inhibit phenobarbital metabolism, increasing plasma concentrations and the risk of toxicity.
  • 25% - 33% excreted unchanged in the kidneys
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18
Q

How long does it takes to achieve therapeutic levels of phenobarbital

A

15 to 20 minutes with phenobarbital IV

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19
Q

Clinical response to phenobarbital

A

>50% reduction in seizure frequency in 60% to 80% of dogs with idiopathic epilepsy

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20
Q

Phenobarbital doses in cats

A

Starting dose of 1.5 - 2.5mg/kg PO / IV q12h suggested

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21
Q

Loading doses of phenobarbital

A
  • If a patient comes with cluster seizures or SE, 16-20mg/kg loading dose can be given
  • Divide in 4-6 equal doses over a 24h period.
  • Intent to achieve serum phenobarbital concentrations of 15-35mcg/mL
  • Monitor closely for extreme sedation (loss of gag reflex), hypoventilation and/or hypotension → delay next dose if that happens.
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22
Q

Serum phenobarbital levels that has risk of hepatotoxicity?

A

>40mcg/mL

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23
Q

Half-life of phenobarbital

A
  • Varies over time - suspected due to autoinduction
  • Dogs - from 37 to 89 hours
  • Cats - from 34 to 43 hours
  • Serum steady-state levels reached in 97% of patients after 5 half-lives
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24
Q

Phenobarbital monitoring

A
  • 2 and 6 weeks after starting phenobarbital
  • 2 weeks after a dose change
  • Due to auto induction of hepatic enzymes - monitor serum levels q6-12 months.
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25
Q

Phenobarbital adverse effects

A
  • Sedation, ataxia / CP deficits → tend to be transient and resolve within 2-3 weeks.
  • PU/PD
  • Polyphagia
  • Hyperactivity / aggression

Less commonly observed - suspected idiosyncratic:

  • Bone marrow suppression (anemia, thrombocytopenia, neutropenia)
  • Hepatotoxicity
  • Superficial necrolytic dermatitis
  • Pancreatitis
  • Hypoalbuminemia
  • Diskinesis and anxiety
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26
Q

Bloodwork changes with phenobarbital

A
  • Increases in ALP - does not mean hepatotoxicity
  • Increases in ALT - less frequent, may be more specific indicator of hepatotoxicity
  • Decreases T4 levels
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27
Q

Anticonvulsant drugs and recommended dosages for dogs

A
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28
Q

Bromide MOA

A
  • Mimics chloride ions in GABA receptors chloride channels → causes hyperpolarization of the neurons, increasing seizures threshold.
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29
Q

Bromide metabolism

A
  • Not metabolized by liver - first line AED in dogs with hepatic dysfunction.
  • Excreted unchanged by the kidneys - renal dz. will increase KBr levels
  • Reabsorbed through Cl channels in renal tubules - amount of Cl in diet can affect KBr clearance - recommended to be on steady diet (regarding Cl intake).
  • Peak absorption - 1.5h after PO admin
  • Oral bioavailability - 46%
  • Unbound to plasma proteins - diffuses freely across cellular membrane
  • Half-life: approximately 25 days in dogs, 12 in cats
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30
Q

Clinical efficacy of KBr

A

Decreases seizure frequency in 72% to 74% of epileptic dogs

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31
Q

Why is not KBr recommended in cats

A

Causes fatal eosinophilic bronchitis - reported in 35% to 42% of cats

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32
Q

KBr doses

A
  • Loading doses of 400 - 600 mg/kg PO/IR over 1-5 days if needed
  • Maintenance - 20-40mg/kg q24h
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33
Q

KBr therapeutic range

A
  • Time to steady state - 2.5-3 months after PO initiation
  • Therapeutic range of 1000-3000mcg/mL when used as mono therapy, or 800-2500mcg/mL when used as add-on therapy.
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34
Q

KBr adverse effects

A
  • Neuro deficits (sedation, agitation or excitability, ataxia, decreased pelvic limb withdrawals, paraparesis)
  • Polyphagia
  • PU/PD
  • Vomiting
  • Pancreatitis
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35
Q

What is bromism / clinical signs / treatment

A
  • Toxic serum concentrations of KBr
  • Clinical signs: altered mentation, ataxia, upper or lower motor neuron paresis.
  • Cut off value for toxicity not established
  • Treatment: dosage reduction or IV 0.9% NaCl
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36
Q

Zonisamide class and MOA

A
  • Sulfonamide - structurally unrelated to all other AED
  • Inhibits voltage-gated Na+ channels
  • Inhibits voltage - gated Ca2+ channels
  • Neuromodulation:
    • Enhancement of GABA function
    • Inhibition of glutamate release
    • Facilitation of dopamine / serotoninergic transmission
    • Increases Ach turnover
  • Neuroprotection - free radical scavenger
  • Inhibitory effect on carbonic anhydrase - does not contribute to antiepileptic effects
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37
Q

Zonisamide metabolism

A
  • Peak serum 2.5-6h post PO dose
  • Oral bioavailability approximately 68%
  • Half-life 17h
  • Protein bound - 40%
  • 10% excreted unchanged in urine
  • 90% liver metabolism by CYP450 - coadministration with PHB increases ZNS clearance by 50% and decreases half-life
  • Time to steady state 4 days in dogs, 7 days in cats
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38
Q

Zonisamide clinical efficacy

A
  • Reported seizure reduction in frequency by 50% in dogs with idiopathic epilepsy
  • 58% to 80% when used as adjunctive therapy
  • 60% when used as monotherapy
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39
Q

Zonisamide doses and therapeutic range

A
  • Monotherapy - 5mg/kg PO q12h
  • Add-on with PHB - 10mg/kg PO q12h
  • Therapeutic range (from human medicine) - 10-40mcg/mL
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40
Q

Zonisamide adverse effects

A
  • Prevalence in dogs (10%-55%)
  • Sedation, ataxia, vomiting, innapetence, KCS
  • Idiosyncratic adverse reactions: acute hepatopathy, renal tubular acidosis, neutropenia with or without concurrent regenerative anemia
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41
Q

Zonisamide monitoring

A
  • 1-2 weeks after treatment initiation, dose adjustment or increases in seizure frequency
  • Collect sample within 1h before the next dose is due
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42
Q

Levetiracetam MOA

A
  • Binds to synapticvesicle protein A (SVA2) → modulates synapticle vesicle fusion and NT release
  • Inhibits Na dependent Cl/HCO3 exchange
  • Antagonizes neuronal hyper synchronization
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43
Q

Levetiracetam metabolism

A
  • 100% bioavailability after PO administration
  • <10% protein binding
  • Readily crosses BBB
  • Half-life time 4-8h
  • Time to steady state - 15-20h
  • 90% excreted in urine via glomerular filtration - 45% unchanged
  • Small portion metabolized by liver (not CYP450) → no autoinduction
  • Long term PHB in epileptic dogs can decrease levetiracetam half-life
  • Does not cause bloodwork changes
  • Does not alter PHB / KBr serum concentrations
  • Recommended in patients with hepatic disease
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44
Q

Levetiracetam doses and therapeutic range

A
  • Starting dose of 20mg/kg PO q8 - if ER → 30mg/kg PO q12h
  • Recommended decrease in dose in patients with renal disease (concerns for decreased clearance)
  • Therapeutic range (humans) - 12-46mcg/mL
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45
Q

Levetiracetam adverse effects

A
  • Sedation, ataxia
  • Aggression
  • Hyporexia
  • Vomiting
  • Transient mild lethargy and hyperemia in cats
  • Honeymoon effect
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46
Q

Levetiracetam monitoring

A
  • Has a high therapeutic index, plasma concentrations not measured.
  • Relationship between serum concentrations of levetiracetam, treatment response and adverse effects has not been established yet.
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47
Q

Gabapentin and pregabalin MOA

A
  • Add-on anticonvulsants, not first line AED
  • Similar mechanism for both
  • Binding on the alpha2-delta subunit of the voltage gated calcium channels, leading to inhibition of release of excitatory NT into the synapse.
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48
Q

Gaba and pregabalin metabolism

A
  • Bioavailability approximately of 80% with a 50mg/kg/day dose
  • About 34% of GABA is metabolized by the liver, and suspected similar for pregabalin.
  • GABA half-life: in dogs, 3-4 hours. Pregabalin - 7 hours.
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49
Q

Gaba and pregabalin clinical efficacy

A
  • Gaba: effective as add-on, with a 55% response rate.
  • Pregabalin - response rate of 64%
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50
Q

Gaba and pregabalin doses and therapeutic range

A
  • Gabapentin - 10 mg/kg q8h
  • Pregabalin - 2-4mg/kg
  • No therapeutic range established.
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51
Q

Gabapentin and pregabalin adverse effects

A
  • Sedation, ataxia - typically mild and may respond to dosage adjustments.
  • As both undergo hepatic metabolism (unlike in humans) - abnormalities in biochemistry might be noted
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52
Q

Is Felbamate used commonly in veterinary medicine?

A

No, it has fallen out of favor

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53
Q

Felbamate MOA

A
  • Inhibition of aspartate receptor-mediated excitation
  • Potentiation of GABAergic activity
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54
Q

Felbamate metabolism

A
  • Bioavailability of near 100%
  • 22-25% protein bound.
  • Liver metabolism
  • 30% excreted unchanged in urine.
  • Half-life in dogs 4-6 hours.
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55
Q

Felbamate doses and therapeutic range

A
  • Dose - 15mg/kg q8h with a maximum dose of 300mg/kg/day (toxic dose)
  • Therapeutic dose (humans) - 60-80mg/L.
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56
Q

Felbamate adverse effects

A
  • Not reported on doses under 300mg/kg/day
  • Ataxia, limb rigidity, tremors, salivation, emesis, weight loss, increased serum liver enzymes, hepatopathy and blood dyscrasias
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57
Q

What’s the mechanism of action of azathioprine

A

Drug class: purine analogue (immunosupressor)
acts on proliferating lymphocytes and induces both B-cell and T-cell lymphopenia.
Azathioprine gets converted to 6-mercaptopurine in the liver.

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58
Q

What’s the mechanism of action of cyclosporine

A

Drug class: Calcineurin inhibitor
Cyclosporine inhibits T-cell activation and prevents synthesis of several cytokines in particular, interleukin 2. It blocks calcineurin-mediated cytokine signaling. Cyclospoine binds to a cyclophilin, immunophilin in the cytoplasm, binding and blocking the function of calcineurin, an enzyme necessary for T-cell activation.

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59
Q

What’s the mechanism of action of Mycophenolate Mofetil

A

Drug class: inhibitor of purine synthesis in both T and B lymphocytes.
acts on DNA metabolism by noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, which is needed for synthesis of guanosine triphosphate. MMF blocks the synthesis of guanosine, thereby enhancing the synthesis of adenosine. Both result in inhibition of purine synthesis in the lymphocytes.
Other effects of MMF in- clude limiting production of nitric oxide, reducing secretion of tumor necrosis factor a, and reducing pro- liferation of T and B lymphocytes

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60
Q

What’s the mechanism of action of Leflunomide

A

Drug class:Antimetabolite Isoxazol derivative
Leflunomide’s immunomodulatory activity is credited to its primary metabolite, A77 1726, that inhibits T- and B-cell proliferation, suppresses immunoglobulin production, and interferes with cell adhesion.

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61
Q

What’s the mechanism of action of IVIG

A

Human intravenous immunoglobulin (hIVIG) involves interaction with inhibitory Fc receptors on phagocytic and antigen-presenting cells by enhancing expression of the inhibitory IgG Fc receptors

hIVIG impedes stimulatory molecules and suppresses antibody production; it interferes with activating complement and formation of membrane attack complex. hIVIG interrupts the complement activation pathway at the C3 stage

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62
Q

Actions of anticholinergics

A
  • Blocks the action of the neurotransmitter acetylcholine at synapses in the central and the peripheral nervous system.
  • Inhibit parasympathetic nerve impulses by selectively blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells.
  • Anticholinergics are divided into three categories in accordance with their specific targets in the central and peripheral nervous system: antimuscarinic agents, ganglionic blockers and neuromuscular blockers
  • Antimuscarinic agents: atropine and glycopyrrolate
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63
Q

Pharmacokinetics - what is and stages

A

It is how the drug moves through the body

Absorption

Distribution

Metabolism

Excretion

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64
Q

Name routes of medication administration

A
  • PO
  • Rectal
  • Topical
  • Intradermal
  • SQ
  • IM
  • IV
  • Inhaled
  • Buccal
  • Sublingual
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65
Q

Name mechanisms of drug absorption

A
  • Passive diffusion. From high to low concentration, no need of transporters.
    • Very small
    • Hydrophobic
  • Facilitated diffusion → require transport proteins. From high to low concentration.
    • Larger
    • Hydrophilic molecules
  • Active transport → From low to high concentration, against concentration gradient. Requires ATP.
    • Larger
    • Hydrophilic molecules
  • Endocytosis
    • Very large molecules like B12
    • Will bind to receptors, then trigger endocytosis.
    • Then exocytosis to be released in the blood.
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66
Q

How does pH affect weak acid drugs absorption?

A
  • Drugs that are weak acids are better absorbed in the nonpolar form (HA) than in the dissociated state (H+ proton + A- polar acid), as in the dissociated state, the acid is negatively charged and will be repelled.
  • To increase the drug being as a weak acid state (HA) we have to increase the amount of protons → acidic environment → reaction will shift towards nonpolar form.
  • Stomach is acid but not much absorption happens in the stomach
  • Proximal duodenum would be the place where most weak acids would be absorbed as there is still some acid from the stomach.
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67
Q

How does pH affect weak base drugs absorption?

A
  • For weak bases, the dissociated state (B + H+) will be the nonpolar as the Base will not have a charge, whereas the BH+ state will be polar, more difficult to be absorbed.
  • We want to decrease the amount of protons to shift the reaction towards the dissociated state → we make the environment more alkaline.
  • Therefore they will be better absorbed in the alkaline parts of the GI → distal ileum.
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68
Q

How can blood flow affect drug absorption

A
  • Less blood flow, less absorption
  • In shock states, there is decreased blood flow to GI tract / skin - less will be absorbed
  • In shock - better IV route
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69
Q

How does total surface area and contact time affect drug absorption?

A
  • If there is diarrhea → increased motility, decreased time → decreased absorption.
  • If there is constipation → increased contact time → increased absorption.
  • Total surface area of intestines is very large - with IBD, gastroenteritis… the microvilli, villi are destroyed, therefore total surface area decreases.
  • If TSA decreases → decreases absorption.
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70
Q

How can p-glycoprotein affect drug absorption?

A
  • People can develop multidrug resistance
  • Imagine a drug taken orally → moves into enterocytes
  • In some situations, on the apical surface of the enterocytes there is a p-glycoprotein, that will spit the drug back into the GI lumen instead of moving it into the blood → decreased absorption.
  • Seen in a lot of multidrug resistant situations.
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71
Q

What is bioavailability?

A
  • Fraction of drug that enters the systemic circulation
  • 100% on IV medications.
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72
Q

How do we calculate bioavailability (F)?

A

F = AUC oral / AUC IV

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73
Q

What factors affect bioavailability?

A
  • Solubility
  • Instability
  • First pass effect
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74
Q

How can solubility affect bioavailability?

A
  • Small molecules, hydrophobic, will be absorbed easily → increased absorption → increased bioavailability
  • Larger molecules, hydrophilic → absorption will be decreased → decreased bioavailability.
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75
Q

How can instability affect bioavailability

A
  • Some medications will be affected by the acid in the stomach, will not be stable in acidic environments, like penicillin g → decreased bioavailability.
  • Some drugs might be affected by enzymes that are excreted in the GIT (proteases) → insulin never given orally because proteases will break it down.
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76
Q

How can the first pass effect can affect bioavailability?

A
  • Drug taken orally → bloodstream → hepatic portal circulation (from GI to liver).
  • Liver will metabolize part of the drug → most of the times inactivates them
  • Then what really gets into the circulation is much less → decreased bioavailability
  • Rectal → very small amount goes to liver.
  • Other routes than oral do not go to liver.
  • Nitroglycerin given PO - only remaining 10%, that’s why it is given sublingual.
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77
Q

What is the pKa of a drug?

A
  • The degree of ionization (pKa) of a drug is a unique physicochemical property that controls its ionization state when in solution.
  • If the drug’s pKa is the same as the pH of the solution it is dissolved in, then 50% of the drug exists ionized and 50% exists nonionized.
  • As the pH of the solution changes, the state of ionization changes as well.
  • We want the pKa to be closer to the pH of the solution where the drug will be absorbed.
  • The pH of extracellular fluid is always going to be within some decimal fractions of 7.4 → drugs with a pKa under 7 (weak acids) will usually be water-soluble.
  • Weakly basic drugs with a pKa closer to 8 will usually be lipid-soluble and will therefore find it easier to negotiate the barrier membranes on their way to their target.
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78
Q

What is the distribution process and what factors affect it?

A
  • Movement of the drug from the systemic circulation to the tissues/organs
  • Blood flow, capillary permeability, protein binding, solubility and volume of distribution
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79
Q

How does blood flow affects drug distribution?

A
  • Organs with more blood flow, like brain and liver and kidneys might get more drug.
  • Organs with less blood flow, less drug (skin, adipose tissue).
  • A patient in shock → decreased blood flow → drug will not be delivered as good → decreased distribution
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80
Q

How does capillary permeability affect drug distribution?

A
  • Organs like liver, bone marrow, spleen → sinusoidal capillaries → very leaky, large fenestrations → drugs can easily leak out
  • Fenestrated capillaries → kidneys, glands → also easy to leak from systemic circulation to tissues.
  • In these organs, distribution is increased as there is an increased capillary permeability.
  • In other organs like brain and muscles → tight junctions, not easy to deliver drugs → decreased distribution. Depends on transporters to facilitate movement of the drug out of the blood, or a very hydrophobic drug, very lipid soluble and very small to be able to pass through the capillaries and into the tissues. Best example is brain.
  • Patients in septic shock → extreme increase in capillary permeability → concentration of drug inside the blood will decrease → increase distribution, decrease serum concentration of drug → high doses of antibiotics as distribution changes.
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81
Q

How does protein binging affects drug distribution?

A
  • Plasma or tissue protein binding → most common plasma proteins.
  • Liver makes albumin and kidneys keep it in the blood.
  • Patients with normal liver and kidney function: should be able to make albumin and keep it in the blood.
  • Albumin → binds to drugs in the circulation.
  • Drug that highly bound to albumin → not much free drug, that is the part that is distributed → decreases distribution of drug. Those drugs will concentrate in plasma.
  • As the free drug moves out of the circulation → concentration decreases, and the drug bounded to albumin acts as a reservoir → releases small amounts into the blood, increasing the free concentration.
  • Opposite → drug that barely binds to proteins → a lot of free drug → concentrate the drug in the interstitial / intracellular fluid.
  • If a patient has kidney disease → albumin is lost in urine → less albumin in blood → increases amount of free drug.
  • If a patient has liver disease → produces less albumin → increases amount of free drug.
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82
Q

How will solubility affect drug distribution?

A
  • Small, nonpolar, hydrophobic molecules → increased distribution → concentrate in tissue spaces.
  • Larger, polar, hydrophilic molecules → lower distribution → concentrate in the blood.
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83
Q

What is the volume of distribution (Vd)?

A
  • The theoretical space / volume that a drug would be distributed
  • Intravascular - interstitial - intracellular
  • If a drug occupies all 3 - large Vd
  • If a drug only stays in the IV compartment - low Vd
  • All factors affecting distribution, they play a role in the Vd of a drug.
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84
Q

Low volume distribution drug example

A
  • Large, polar, hydrophilic molecule, highly protein bound…
  • Imagine plasma 4L, interstitial fluid 8L, and intracellular 12L (total of 24L).
  • Out of those 24L, the drug will stay IV - in 4L → that will be the Vd, very concentrated in the plasma.
  • Example: warfarin, Vd=8L → small. It concentrates in the plasma → supposed to interact with clotting proteins, is what we want.
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85
Q

Intermediate volume distribution drug example

A
  • Mild protein binding, low molecular weight, still hydrophilic (has some charge)
  • Will move out of the vascular space into the interstitial space.
  • IV 4L, interstitial 8L, intracellular 12L → this drug would occupy 2 compartments → Vd - 8 + 4L = 12L.
  • Maybe a small amount in the cells but primarily IV and interstitial
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86
Q

High volume distribution drug example

A
  • Hydrophobic, small molecule, not protein bounded, not polar
  • Drug will distribute in all 3 compartments → large Vd = 24L (following others examples).
  • Example: chloroquine - Vd = 150,000L → higher than the total volume → barely stays in the plasma, distributes everywhere.
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87
Q

How can we calculate Vd?

A

Vd = F x dose / C = Liters

Where:

F: bioavailability (intravenous would be 1 => 100%)

Dose given (total mg)

C: peak plasma concentration (mg/L)

Vd is in L / Kg => divide result by weight to have L/kg.

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88
Q

What can the liver do to drugs / toxins?

A
  • Can convert toxins into non toxic metabolites
  • Can convert a prodrug and convert it in active drug
  • Can convert an active drug and convert it in an inactive drug - to be excreted in urine / feces
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89
Q

How many phases are necessary to convert an active metabolite in a inactive one?

A

Phase I and phase II.

Not all drugs do all phases in same order.

Some drugs will only do phase I, some only phase II, some will do phase II then phase I.

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90
Q

Phase I of biotransformation

A
  • In hepatocytes → smooth endoplasmic reticulum and mitochondria → inside them → heme containing enzymes → CYP450 system (cytochrome family)
  • 2 different types of enzymes in the CYP450 that metabolize 70% of drugs → CYP3A4 and CYP2D6
  • CYP450 → can oxidate, reduce or hydrolyze. The goal is to take a drug that is nonpolar and converted into something polar. Something lipid soluble into something water soluble → so it is easily excreted and not reabsorbed.
  • It does that adding an oxygen or OH group.
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91
Q

What factors can affect phase I of biotransformation?

A
  • Polymorphism → different genes that will make CYP450 more or less effective. That will decrease the concentration of active drug → decreased therapeutic effect, will need more drug. Opposite → slow metabolism → more active drug remaining in blood → toxic side effects.
  • CYP450 inducers → when someone takes more than one medication → a patient on warfarin → if we give a CYP450 inducer → warfarin will be metabolized faster, decreasing the amount of effective warfarin → higher risk of clotting. Other inducers - phenobarbital, rifampin, phenytoin.
  • CYP450 inhibitors → will do the opposite, decrease the activity of CYP450 → example of warfarin → if we give an inhibitor, the concentration of active warfarin in plasma will increase → risk of bleeding, toxic effects. CYP450 inhibitors: erythromycin, omeprazole…
  • Liver disease - main place where metabolism happens (minimal in kidneys, lungs and intestinal cells). If the liver is diseased / failing → not able to metabolize correctly as the CYP450 will decrease in number / efficacy → develop toxicity. Age: babies and older individuals, CYP450 activity is decreased.
  • To consider → if instead of deactivating a drug, the metabolism is to convert a prodrug into its active form, the CYP450 inhibitors and inducers would have the opposite effect → inducers would increase the amount of active drug, increasing risk of toxicity, and inhibitors would decrease the amount of active drug, decreasing its effectivity.
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92
Q

Phase II biotransformation

A
  • Take the drug that maybe is not polar enough, not water soluble enough, and we make it more polar and more water soluble.
  • Enzyme transferases → can add different groups (methyl, acetyl, sulfa, gluthatione, glucoronate) into the inactive molecule → CONJUGATION REACTIONS.
  • Gives more polarity to the drug → easily to excrete into feces with bile or in the urine.
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93
Q

Factors that affect drug distribution

A
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94
Q

What factors affect oral bioavailability?

A
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95
Q

How can sepsis affect Vd?

A
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96
Q

What is clearance of a drug?

A

What comes in vs what comes out of a drug

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97
Q

What is the extraction ratio (E)?

A

Fraction of a drug / molecule that is eliminated by an organ

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98
Q

How can sepsis alter clearance?

A
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99
Q

What is the elimination of a drug?

A
  • Moving the drug out of the body
  • Rate of elimination influences duration of action
  • Mainly through kidneys and biliary tract - enterohepatic circulation, renal dz will affect drug clearance.
  • Less significant through saliva, lungs
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100
Q

How can sepsis affect the pharmacokinetics of medications?

A
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101
Q

Define drug absorption

A

Absorption is the process of drug movement from the site of drug administration to the systemic circulation. Various processes underlie the successful absorption of drugs. They include passive diffusion, facilitated diffusion, active transport, and endocytosis. Drug absorption is quantified in terms of bioavailability

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102
Q

Define bioavailability (F%)

A

Bioavailability is the extent to which absorption occurs. In other words, is the fraction of the administered drug that reaches the systemic circulation in the unchanged form. Compares extravascular administration with IV administration, using AUC.
Ex. Buprenorphine given transmucosal in cats have 40 to 50% bioavailability

F = AUC po / AUC iv

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103
Q

The ___________ tells us about drug exposure. Is most usefl to calculate bioavailability and for some PK/PD modeling of antibiotics

A

AUC

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104
Q

Define drug distribution

A

movement of drug from blood to sites in the body (site of action)

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105
Q

T/F Most of the anesthetic drugs are hydrophilic and have a low volume of distribution

A

FALSE - most are lipophilic with a large Vd

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106
Q

If the volume of distribution is similar to the plasma volume, the medication _______ (does/does not) distribute significantly out of the plasma compartment

A

does not

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107
Q

How can you calculate the volume of distribution of a drug?

A

Vd = dose given/Cp (plasma concentration of the drug)

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108
Q

List hydrophilic antibiotics

A

Aminoglycosides (gentamicin, tobramycin, amikacin, neomycin)
Beta lactams (penicilins, cefalosporins and carbapenems)
Glycopeptides (vancomycin)

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109
Q

If a septic patient with vasculitis and hypoalbuminemia is receiving Amoxicillin and clavulanic acid, you would expect that the volume of distribution of this medication would _____________(increase/decrease). Based on that, plasma concentrations would _____________ and you’ll need to administer a ________ (higher/lower) dose to achieve a target dose.

A

Vd = increase
Plasma concentration = decreases
Dose needs to be increased

* Remember this is a hydrophilic antibiotic (so this applies for hydrophilic drugs, lipophilic drugs are less affected by this)
* Fluid overload can cause the same changes

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110
Q

List lipophilic antibiotics

A

Macrolides
fluoroquinolones
Lincosamides

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111
Q

If you have a drug that is 30% protein bound and another drugs that is 70% protein bound, which one has a higher volume of distribution?

A

the drug that is 30% protein bound

Low protein binding = increased vD

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112
Q

T/F - The volume of distribution of a drug can be calculated only if the drug was given IV

A

TRUE - if drug is given via an extravascular route, the absorption of the medication will be unknown

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113
Q

Dose/AUC = ????

A

Clearance

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114
Q

Which drugs have a high extraction ratio in the liver? Why is this important?

A

Opioids
Lidocaine
Beta blockers
Benzodiazepines
Alpha-2 agonists

It matter because the blood flow to that organ would be the main limiting factor for drug extraction.
Then, hypotension, vascoconstriction, hyperdinamic shock –> will alter the clearance of these medications

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115
Q

A drug takes ____ half lifes to reach steady state

A

3 to 5

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116
Q

Inhibitors of CYP450

A

Ketoconazole

Omeprazole

Cimetidine

Fluoxetine

Fluoroquinolones

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117
Q

Inducers of CYP450

A

Phenobarbital

Rifampin

Glucocorticoids

Omeprazole

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118
Q

What is the usefulness of half life

A

can be used to design dose regimens
Can be used to determine time of a medication to reach steady state
Tells us how long before a drug is eliminated

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119
Q

The majority of drugs, it takes ___ half lifes to be eliminated

A

3-5 half lives for 87 to 97% to be eliminated

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120
Q

What is the steady state of a drug?

A

The rate going in equals the rate going out

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121
Q

What is the first pass metabolism?

A

Phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation. It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall.

After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver thus may greatly reduce the bioavailability of the drug.

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122
Q

What are the 2 principal factors that affect pK?

A

Volume of distribution

Drug clearance

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123
Q

T/F Antimicrobials need to reach effective concentrations in the interstitial fluid of tissues, as this is the site of most infections

A

TRUE

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124
Q

T/F An increased Vd may result in a greater loss of antimicrobial from the intravascular space, therefore actually increasing the concentration in the interstitial space.

A

TRUE

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125
Q

Is Vd increased or decreased in critically ill?

A

Increased

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126
Q

Why is Vd increased in critical illness?

A

o Is a result of critical illness-related pathophysiology (eg, vascular dysfunction, microvascular failure, fluid extravasation) and medical interventions, including fluid resuscitation.

o The effect on changes to Vd is predominantly restricted to hydrophilic drugs.

o It has been recommended to administer loading doses of hydrophilic antimicrobials in critically ill human patients to ensure that therapeutic concentrations are achieved.

o It has also been recommended to administer hydrophilic antimicrobials as extended infusions.

o The Vd for lipophilic drugs is usually high and often unchanged in critically ill patients, and a loading dose is not recommended.

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127
Q

For all antimicrobial classes, including concentration-dependent antimicrobials, an ________ Vd can prolong the time needed to reach therapeutic concentrations.

A

Increased

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128
Q

What happens when the patient starts recovering with the Vd?

A

With recovery from infection (and correction of the changes associated with critical illness), the Vd will return to normal resulting in the need for dose modifications throughout treatment during longer courses of antimicrobials.

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129
Q

How is the clearance of hydrophilic antibiotics? and the lipophilic ones?

A

The clearance of hydrophilic agents is predominantly via renal mechanisms while hepatic clearance is more common for lipophilic agents.

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130
Q

What is augmented renal clearance (ARC)?

A

The GFR in critically ill patients increases as a result of increased renal perfusion due to high cardiac output and low systemic vascular resistance, therefore increasing antimicrobial clearance.

131
Q

When is augmented renal clearance most typically seen?

A

o In critically ill patients with normal serum creatinine concentrations

o Most common in patients with trauma, sepsis, burns, hematological malignant disease, or pancreatitis.

132
Q

What is minimum inhibitory concentration (MIC)?

A

o The lowest concentration of an antimicrobial agent that will inhibit the visible growth of a microorganism after overnight incubation.

o Most laboratories report bacterial susceptibility to antimicrobials as susceptible, intermediate-susceptible, or resistant.

o These classifications are made based on MIC breakpoints

133
Q

Why do we need to know the MIC of the antibiotic we want to administer?

A

o To determine the dose needed

o Defines how much antimicrobial exposure is necessary to achieve predefined PK/PD targets that would be associated with maximal effectiveness

134
Q

Infections in human ICU patients are often caused by pathogens with _______ MICs than those encountered in other clinical settings.

A

Higher

135
Q

A study comparing critically ill people to other patients showed that the MIC needed to kill 90% of gram-negative isolates was _________ times higher in those that were critically ill.

A

4-8

136
Q

T/F Once antimicrobials have been started, the prevalence of MDR reduces significantly

A

FALSE - A study of 74 dogs who were admitted to a tertiary referral veterinary teaching hospital with bacterial cultures submitted within the first 48 hours of admission were found to have a multiple drug resistant (MDR) isolation rate of 27%. Repeat cultures that were then performed after 48 hours of hospitalization showed that the isolation of MDR infections had increased to 59%. This finding highlights the high prevalence of MDR development in critically ill patient populations, even after antimicrobial therapy has been initiated.

137
Q

What are time-dependent antibiotics?

A

o With time-dependent antimicrobials bacterial killing occurs when the drug concentration exceeds the MIC of the infecting pathogen.

o This is often expressed as time above minimum inhibitory concentration (T > MIC), or the amount of time that the serum concentration of an antimicrobial agent is greater than the MIC of the infecting organism.

o Ideally this concentration would exceed the MIC for as much time as possible (ie, a T>MIC as close to 100% as possible).

o Maintaining a T>MIC of 100% is more important in critically ill patients that have altered or diminished immune function, as healthier patients will still possess adequate immune function to combat an infection in the event of a serum antimicrobial concentration that is below the MIC.

138
Q

When is maximal bacterial killing achieved with time-dependent antibiotics?

A

When antimicrobial concentrations are maintained at 4–5 times the MIC of the infecting pathogen.

139
Q

What is a concentration-dependent antibiotic?

A

o The maximum antibacterial effect occurs when the peak drug concentration exceeds the MIC several times (>8–10 times).

o These antimicrobials generally work through the inhibition of DNA synthesis and therefore inhibit bacterial growth.

o Following their administration, there is sustained suppression of bacterial growth due to the need for the bacteria to synthesize new proteins before their growth can continue.

o This is a theory known as the post-antibiotic effect (PAE).

o The duration of this suppression is what dictates the frequency with which the antimicrobial will need to be given (i.e., once a day administration for aminoglycosides).

o The PAE may be absent for some organisms or some patients, especially those that are immunocompromised. The duration of PAE varies with each antimicrobial, each pathogen, and each patient.

140
Q

What are the 3 pillars of effective antimicrobial therapy?

A

o Early administration of antimicrobials

o The appropriateness of the initial empirical antimicrobials selected

o Early achievement of therapeutic levels (ideally after the first dose)

141
Q

What are the main goals of antimicrobial therapy?

A

o Rapidly reduce the microbial load

o Minimize the time that systemic inflammatory stress is able to develop.

142
Q

T/F A retrospective analysis of septic shock in people suggested that delaying the initial administration of an effective antimicrobial is the single strongest predictor of non-survival.

A

TRUE

This study showed that every 1 hour of delay in appropriate antimicrobial administration in the first 6 hours after hypotension is documented, led to a decrease in survival by 7.6%.

143
Q

What happens in people when the incorrect antibiotic is started empirically? Is it the same in SA?

A

o Recent data suggests that inappropriate empiric antimicrobial treatment reduces survival 5-fold in serious infections with septic shock.

o Black et al showed that dogs in an intensive care population, on average, received 3 antimicrobials per patient throughout their hospitalization, with ampicillin and enrofloxacin being the most commonly used.

o When these antimicrobial therapies were chosen empirically they were determined to have been appropriate in 75% of cases once susceptibility reporting was available.

o A similar study showed empiric antimicrobial choices in dogs with septic peritonitis to be appropriate in only 52.6% of cases. No significant difference in survival to hospital discharge between dogs treated with appropriate antimicrobial choices (58.5%) compared to those that received inappropriate antimicrobial choices (52.6%), which is in contradiction to similar human studies.

o This dichotomy is suspected to be due to a small sample size (78 dogs) and only including patients with septic peritonitis and not other forms of sepsis.

144
Q

In one study, dogs that had been started on antimicrobials before presentation to the hospital were found to have _______ of bacterial isolates that were resistant to the initial antimicrobial therapy.

A

57.4%

o It may be prudent to avoid recently administered antimicrobials as part of the initial empiric therapy.

o It is suggested that a 3-month antimicrobial-free period should elapse before a patient can be considered antimicrobially naïve, however this has not been scientifically validated.

145
Q

When we are waiting for C&S sometimes we need to start antibiotics empirically. What are the factors we should consider when doing that?

A

o The empiric antimicrobial choice should be made based on the location of the infection and the suspicion of the most likely infecting bacterial organisms (ie, facultative and obligate anaerobes from gastrointestinal sources).

o Geographical location, time of year, and common bacterial isolates from within a hospital should also be taken into consideration.

o It is also important to consider the susceptibilities of previously documented infections in a patient, especially if those microbial agents had known drug resistance.

o Also suggested to avoid antimicrobial classes that had been administered in the previous 3 months.

o Cytologic analysis from the site of infectio is a quick and easy diagnostic that can be used to help narrow empiric antimicrobial choices based on the microbial morphology (cocci vs bacilli) and staining properties (Gram- positive vs Gram-negative).

146
Q

What are the advantages of choosing to combine more than 1 antimicrobial?

A

o Increased spectrum of coverage

o Can prevent the emergence of resistances

o Possible advantage of synergism between the 2 antibiotics → improving bacterial killing → not proven on outcome

147
Q

What are the disadvantages of choosing to combine more than 1 antimicrobial?

A

o Increased risk of toxicity / adverse effects

o Increased risk for development of resistances - increased risk of MDR development can occur when susceptible organisms are killed by the selected antimicrobial regimen, but the growth of resistant subpopulations of bacteria occurs.

o Increased cost

o Possible antagonism between both medications

148
Q

Why combination therapy of antibiotics is recommended in CI patients?

A

o Healthy patients that are immunocompetent can successfully suppress an emergent infection → lower doses of antimicrobials are often successful despite the potential for emergent resistance.

o Critically ill patients may lack these means of dealing with emergent bacterial populations, making new and concurrent infections more likely.

o Resistant organisms that develop can then be shed into the environment, increasing the risk for spread through an ICU population.

o Therefore, empiric combination therapy is recommended to be initiated for the first few days of treatment, however it must be adjusted to a narrower regimen in the first 72 hours, if possible, to minimize selection pressure toward resistant organisms.

o In a study of human patients with septic shock, combination therapy of a beta-lactam with other antimicrobials was associated with a decrease in 28-day mortality compared with beta-lactam monotherapy.

149
Q

What approaches can we have when we are deciding which antimicrobial to use, regarding escalation / de-escalation therapy?

A

o Judgment that the likely organism has a normal susceptibility and can therefore be treated as such with the possible need for escalation to second-line drugs after microbial identification.

o Or a judgment based on local microbiology patterns and clinical presentation, that the infecting organism may be MDR and should be treated as such, with possible de-escalation to a simpler antimicrobial regimen after antimicrobial susceptibilities are known.

o The latter approach is used in ICUs to ensure all possible causative organisms are initially covered.

o Several human studies have shown that de-escalation of antimicrobial therapy is associated with improved outcomes.

150
Q

If we need to de-escalate, when should we do it?

A

Should occur within 48–72 hours after initiation of treatment if a plausible pathogen is identified or if the patient stabilizes clinically to reduce the potential for antimicrobial resistance emergence.

151
Q

T/F Early appropriate antimicrobial therapy is the central element in the management of septic shock, but clearance of pathogens will not begin until therapeutic levels of the antimicrobials in the circulation are reached.

A

TRUE

152
Q

How could we optimize the obtainment of pK/pD targets on time-dependent antimicrobials?

A

o For time-dependent antimicrobials the key PK parameter for optimization of pathogen clearance is the T>MIC.

o There are two main approaches used outside of standard antimicrobial dosing to increase the probability of achieving therapeutic targets in critically ill patients: the use of continuous infusions of time-dependent antimicrobials, and making dose adjustments during treatment guided by therapeutic drug monitoring.

o Some experts advocate using both approaches together.

153
Q

What is therapeutic drug monitoring?

A

o Relies on direct measurement of serum antimicrobial concentrations with timely reporting back to the clinician.

o Adjustments can then be made to the antimicrobial treatment regimen by direct comparison of the measured value to a therapeutic target (ie, MIC).

o TDM has traditionally been used to minimize toxic effects, but in critically ill patients it can be used for the determination of antimicrobial dosing in the presence of severely altered PK.

o A randomized, controlled human trial showed that a dedicated TDM intervention in a general patient group significantly reduced their length of hospitalization compared to patients that did not have TDM (20.3 vs 26.3 days, respectively).

o Studies with quinolones, 𝛽-lactams, glycopeptides, and linezolid have shown advantages in clinical cure, mortality, or both associated with achievement and maintenance of target PK/PD indices.

154
Q

What does therapeutic drug monitoring (TDM) normally measures?

A

o Total drug concentrations (bound and unbound drug), sometimes making interpretation difficult.

o The concentration of unbound drug in a blood sample is important for accurate interpretation of drug exposure, as it is only the free drug that is microbiologically active.

o Knowledge of free concentrations is especially important for antimicrobials that are highly protein-bound in plasma.

o Furthermore, because most infection occurs in tissue interstitial fluid, the antimicrobial concentration measured in the plasma is actually often only a surrogate for the true concentration at the site of infection and may over or underestimate the actual interstitial fluid concentration.

o Low interstitial fluid concentrations, as much as one- tenth than is observed in plasma, have been described.

155
Q

_________ courses of antimicrobials are associated with MDR pathogen selection and spread, increased risk of toxicity, and higher costs.

A

Longer

156
Q

Antimicrobial courses that are too ________ risk inadequate bacterial eradication and the possibility of relapse.

A

Short

157
Q

What is antimicrobial resistance?

A

A measure of the decreased ability of an antimicrobial agent to kill or inhibit growth of a microorganism.

158
Q

What is a breakpoint of an antimicrobial susceptibility test (AST)?

A

o An antimicrobial concentration used to interpret a MIC for a given microorganism.

o An organism is said to be susceptible to an antimicrobial if the MIC is below the breakpoint for that antimicrobial.

o The clinical breakpoint is normally set at the highest MIC achievable that still inhibits growth of that microorganism.

159
Q

What types of resistance can bacteria exhibit?

A

o Three: intrinsic, circumstantial and acquired.

160
Q

What is intrinsic resistance of a bacteria?

A

o An inherent feature of a microorganism that will result in lack of activity of an antimicrobial drug or class drug.

o Example: P. aeruginosa - resistant to majority of B lactam antibiotics except for a few designed as anti-Pseudomonas.

o Example: all gram negative resistant to vancomycin, cannot penetrate their cell membrane.

161
Q

What is circumstantial resistance?

A

o When an in vitro test predicts susceptibility but in vivo, the atb lacks clinical efficacy.

o Maybe due the lack of penetration to the site of infection or inability to work due to local pH (inactivation in acid urine)

162
Q

What is acquired resistance?

A

o A change in the phenotypic characteristics of a microorganism.

o Through acquisition of efflux pumps, antimicrobial degrading or modifying enzymes or reduced uptake into a cell, amongst others.

163
Q

Which type of resistance leads to the development of many MDR?

A

Acquired

164
Q

Define multidrug resistant (MDR) organism

A

o Organism not susceptible to at least one agent, in 3 or more classes of antimicrobials, to which they are usually susceptible.

165
Q

What is an extensively drug resistant (XDR) organism?

A

Organisms that are only susceptible to only 1 or 2 classes of antimicrobials.

166
Q

What is a pan drug resistant organism (PDR)?

A

Organisms not susceptible to all known or licensed antimicrobials currently available.

167
Q

What is the most common way for a laboratory to determine the MIC?

A

Microdilution test

168
Q

What is the minimum bactericidal concentration (MBC)?

A

The MIC in which 99.9% of the isolates are inhibited.

169
Q

Determining if an organism is susceptible, intermediate or resistant is based on what?

A

On the breakpoint concentration for that specific bacterium.

170
Q

if the MIC is ______ than the susceptible breakpoint, it is considered __________

A

Less

Susceptible

171
Q

If the MIC is _________ than the resistant breakpoint, then it is considered _________

A

Greater

Resistant

172
Q

T/F MIC’s between the susceptible and resistant breakpoint are deemed intermediate

A

TRUE

173
Q

What is the 90/60 rule in human medicine for antibiotic therapy?

A

o Used to predict whether a bacteria will respond to treatment or not

o In general, 90% of patients will have a favorable response to therapy if the classification is susceptible.

o However, approximately 60% of the patients will still have a favorable response if classified as resistant.

174
Q

What would be the ideal antibiotic in critically ill?

A

o Minimal side effects

o Can be given IV

o Is bactericidal.

175
Q

If two drugs are equal in their potential toxicities and distribution to the tissue, we should chose the one with the ________ MIC to breakpoint ratio, to help prevent resistance development and have a higher likelihood of treating the infection

A

Lower

176
Q

What is the goal on concentration dependent antibiotics regarding the highest concentration (Cmax)?

A

To have a Cmax / MIC ratio of >10

177
Q

Example of synergistic effect with antimicrobials?

A

o B-lactams + aminoglycosides

o B-lactams will create holes in the bacteria cell membrane, allowing higher concentrations of aminoglycosides in the bacteria.

178
Q

What is one of the limitations of the classification as susceptible?

A

o That pK data might be based in human studies.

o Ciprofloxacin - in humans, oral bioavailability of 80-90%, in dogs is 30-40% and in cats only 20%.

o Should be classified as resistant in vetmed.

179
Q

When should we chose an antibiotic that has been classified as intermediate?

A

o When the only antimicrobials listed as susceptible are inappropriate for the patient (like ahminoglycosides in a patient with renal disease), or no drug is listed as susceptible.

o We can also choose an intermediate classified drug and by altering the dose, turn it into a susceptible one - like enrofloxacin in dogs, instead of 5-10mg/kg q24h, increase to 15-20mg/kg q24h - reserved when no other atb is listed as susceptible.

180
Q

Should we use antibiotics labeled as resistant

A

o No.

o Call lab and ask to run a extended spectrum tray to find the appropriate atb.

o For some G+, it is possible to use 2 resistant to convert to susceptible → for example, amino glycoside + penicillin with Enterococcus.

o Another possible synergistic combination → use 2 different B-lactams for G+ and G- as well.

181
Q

Spectrum of ampicillin + sulbactam

A

G+, G- and anaerobes

182
Q

What is the spectrum of enrofloxacin?

A

G-

183
Q

T/F - Enrofloxacin is bacteriostatic but at higher doses can be bactericidal

A

TRUE

184
Q

T/F If we give sulfonamides or trimethropin separately they are bacteriostatic, but when combined they are bactericidal

A

TRUE

185
Q

Cephalosporin comparsion

A
186
Q

What is the peak concentration over MIC?

A

The highest concentration reached with a concentration dependent antibiotic

The highest the concentration, the more inhibition - Cmax/MIC ration

187
Q

Bactericidal vs bacteriostatic antibiotics

A
188
Q

What is cilastatin?

A

o Is a dehydropeptidase inhibitor used together with imipenem

o Renal dehydropeptidase degrades the antibiotic imipenem → can cause renal toxicity, cilastatin decreases it.

o Meropenem is resistant to the dehydropeptidase

189
Q

How do several classes of bacteria co-exist in the GI tract?

A

o Each microbe maintains an ecologic niche by competing for nutrients and actively suppressing surrounding growth through secretion of antibiotics.

o Self destruction does not occur because genes encoding antibiotic secretion generally accompany genes that impart resistance.

190
Q

With which number of CFU should we suspect resistance?

A

o When the population of bacteria reaches or exceeds 10^6 to 10^8 CFU, whether the population is a commensal resident or an infecting pathogen

191
Q

Name common resistant organisms

A

o MRSA - methicillin-resistant Staphylococcus aureus

o VRE - Vancomycin resistant Enterococcus

o FQRP - Fluoroquinolone resistant Pseudomonas and E. coli.

o VRSA - Vancomycin resistant Staphylococcus aureus

o Fluoroquinolone-resistant Clostridium difficile

192
Q

Define nosocomial infection

A

Infections arising more than 48h after hospital admission.

193
Q

Four primary drivers on antibiotic administration that reduce the incidence of C. difficile

A

o Timely and appropriate initiation of antibiotics

o Appropriate administration and deescalation of antibiotics

o Data monitoring, transparency and stewardship infrastructure

o Availability of expertise at the point of care.

194
Q

T/F The use of broad spectrum drugs increases the risk of resistance

A

TRUE

195
Q

Genitourinary tracts are often infected with _________ whereas abdominal infections are generally caused by ___________ initially, followed by_________

A

G- aerobes

G- aerobes

Anaerobes

196
Q

When should we consider anaerobic coverage?

A

o In selected infections, like osteomyelitis

o In infections involving deep, isolated areas and hollow organs

o In those associated with a foul smell and marked inflammation (abscess)

197
Q

Granulocytopenic or otherwise immunocompromised patients are more likely to be infected by__________

A

G- aerobes

198
Q

T/F Combination therapy should be considered routinely for treatment of organisms often associated with multidrug resistance.

A

TRUE

(Pseudomonas aeruginosa, Enterococcus spp. and MRSA)

199
Q

How much should it be the Cmax/MIC on concentration dependent antibiotics?

A

10 to 12, and higher for more difficult infections like P. aeruginosa.

200
Q

What is the area under the inhibitory curve (AUIC) of an antibiotic?

A

o The ratio of the AUC (area under the curve for 24h, which is influenced by both dose and interval) to the MIC.

o An AUIC of over 100 to 125 is generally associated with bacterial killing and decreased resistance.

o Treatment for some infections, the dosing regime might be designed to maximize both the Cmax:MIC (higher dose) and the AUC:MIC (shorter dosing interval)

201
Q

How many levels of drug penetration exist in normal tissues?

A

o Three

o Sinusoidal capillaries → primarily in adrenal cortex, pituitary gland, liver and spleen - essentially no barrier to bound or unbound drug movement.

o Fenestrated capillaries → in kidneys and endocrine glands. Contain pores that do not present a barrier to unbound drug, and movement is facilitated between plasma and interstitium.

o Continuous (non fenestrated) capillaries → brain, CSF, testes, prostate, muscle and adipose tissue → present a barrier of endothelial cells with tight junctions that preclude drug movement.

202
Q

For infections in tissues with continuous capillaries, should we do any adjustments on our antimicrobial therapy?

A

o Yes. The dosing regime of water-soluble drugs (b-lactams, aminoglycoside, selected sulfonamides and tetracyclines) should be adjusted for potentially poor drug distribution into the site of infection → doses sometimes adjusted up to 10 fold in treating human CNS.

203
Q

Based on human studies, only _________ of B lactams or aminoglycosides in plasma reach bronchial secretions, compared with ____________ of lipid soluble durgs

A

2-30%

30-80%

204
Q

An increase in the volume of distribution will __________ the plasma concentration, and vice versa

A

Decrease

205
Q

Most common two conditions in critically ill that will cause increase of Vd

A

Septic shock and trauma

206
Q

How should we monitor for aminoglycosides drug concentration?

A

o Collect a sample at peak serum concentration, 1-2h after administration

o Collect a second sample 4-6h later to monitor through concentration

207
Q

Hypoalbuminemia contributes to a ______________ antimicrobial exposure, even for drugs that are not significantly protein bound

A

Decreased

o Probably due to peripheral fluid retention and increased Vd

208
Q

What should we do regarding the dose of antibiotic if hypoalbuminemia is present?

A

o Dosage increase of 1.5-2 fold are indicated

209
Q

Will volume of distribution affect drug elimination?

A

o Yes

o Elimination half-life is affected by both volume of distribution (directly proportional) and clearance (inversely proportional)

210
Q

What happens with drug clearance in critical illness?

A

o CI normally decreases drug clearance

o Except septic shock, as it is a hyper dynamic state, is frequently associated with an increased clearance

211
Q

T/F Acute inflammation may initially increase drug delivery to the site of infection

A

TRUE

212
Q

What is the inoculum effect?

A

The inoculum effect (IE) is a laboratory phenomenon that is described as a significant increase in the minimal inhibitory concentration of an antibiotic when the number of organisms inoculated is increased.

213
Q

What is the impact of a larger inocula?

A

o More bacterial targets and thus require more drug molecules (higher doses)

o Greater risk of spontaneous mutation resulting in resistance.

o Produce greater concentrations of destructive enzymes.

o Example: production of extended-spectrum B-lactamases (ESBL) results in cephalosporin resistance with a larger (10^7) than with a smaller (10^5) inoculum.

214
Q

Examples of soluble mediators that can be released by organisms

A

o Hemolysin, epidermolytic toxin, leukocidin.

o May damage host tissues or alter host response

215
Q

What is a biofilm?

A

o A community that effectively allows a single-cell microbe to become a multicellular organism.

o It consists of micro colonies of both pathogenic and host microbes embedded in a polysaccharide produced by microbes adhering to flat surfaces.

o Symbiosis and survival are supported through sophisticated communication and complex patters of antimicrobial resistance as well as an ability to avoid host immune response.

o Organisms within the community are often quiescent and non-responsive to antimicrobial therapy.

o Translocation of the biofilm microflora to sterile tissues may ultimately cause infection

216
Q

Why normally antibiotics are safe for the host? are there any exceptions?

A

o Because host cells are eukaryotic whereas bacterial targets are prokaryotic.

o Yes, drugs that target shared structures such as cell membranes (polymyxin).

o Aminoglycosides are nephrotoxic, related to the duration of exposure.

217
Q

If aminoglycosides cause nephrotoxicity, which drug might help?

A

NAC may decrease damage

218
Q

Do all FQ cause retinal damage in cats?

A

o No. Marbofloxacin, orbifloxacin and pradofloxacin appear not to cause retinal toxicity, even when administered at dosages exceeding the recommendations.

219
Q

Advantages of deescalation

A

o Reduce cost

o Reduce risk of adverse events

o Reduce risk of developing antimicrobial resistance

o Decrease incidence of infections related to antimicrobial use, like C. difficile diarrhea, superinfections with MDR or candidiasis.

220
Q

What antimicrobials are B lactam?

A

o Penicillins, cephalosporins and carbapenems

o All of them have a b-lactam ring in their structure, essential for their biological activity.

221
Q

How do B lactam do their action?

A

o They bind to and inhibit the transpeptidases and peptidoglycan-active enzymes, collectively referred as penicillin-binding proteins, that catalyze the cross-linking of the glycopeptides which form the bacteria cell wall.

o They are bactericidal, but they do require the cells to be actively growing to be efficacious (that is why there is antagonism with antibiotics that inhibit protein synthesis)

222
Q

The difference in susceptibility to B lactams between G+ and G- depends on what?

A

o Number and type of drug receptors

o Amount of peptidoglycan present (G+ have a much thicker wall)

o Amount of lipid on cell wall.

223
Q

T/F Ampicillin has poor oral bioavailability

A

TRUE

224
Q

T/F - Despite their large volume of distribution in interstitial fluid, most of the β-lactams do a poor job of crossing biologic membranes, and their concentration in the eyes, testes, brain, and prostate may be only one tenth of the serum concentration

A

TRUE

225
Q

If b-lactam do not cross well biological membranes, why are they sometimes indicated for certain infections within the CNS?

A

o Because bactericidal levels of drug can be found in the CNS, particularly when there is inflammation of the meninges and a decrease in the blood-brain barrier.

226
Q

T/F Most β-lactams are excreted actively by the liver. As a result, urine levels can be lower than those seen in serum

A

FALSE - They are excreted by the kidneys and concentration in urine can be severalfold higher than in plasma.

227
Q

Which bacteria can typically produce B lactamase?

A

o Staphylococcus and most G- rods

o Produce a β-lactamase enzyme that inactivates β-lactams by cleaving the β-lactam ring

228
Q

Extended-spectrum β-lactamase (ESBL)

A

o Production by gram-negative organisms of enzymes that can hydrolyze penicillins, cephalosporins, and aztreonam to variable extents.

o ESBL production does not confer resistance to the carbapenems

o ESBL-producing organisms have been identified in clinical veterinary patients and have been found in the feces of healthy cats and dogs in the community.

o The risk of fecal carriage of ESBL-producing organisms was increased in animals that had received antimicrobials in the 3-month period before testing.

229
Q

How is the resistant mechanism of MRSA?

A

o Some bacteria can become resistant to β-lactam antimicrobials by altering their PBPs. (penicillin-binding proteins)

o The PBPs can still cross-link glycopeptides but prevent the binding of β-lactam antimicrobials.

o The most important instance if this type of mutation is the acquisition by Staphylococcus spp of a gene known as mecA that codes for PBP-2a.

o As a result of this alteration in PBPs, staphylococci become resistant to all commonly available β-lactam antimicrobials (with the exception of fifth-generation drugs) and are known as methicillin-resistant staphylococci.

230
Q

Penicillin G

A

o Has a good spectrum of action against gram- positive and anaerobic organisms, with the exception of some Staphylococcus spp.

o Is synergistic with aminoglycosides, and this combination may be effective against staphylococci.

o Penicillin G is the drug of choice for treatment of streptococcal infections (e.g., necrotizing fasciitis), clostridial infection, and actinomycosis.

231
Q

Extended-spectrum penicillins (=aminopenicillins)

A

o They are less active against G+ and anaerobic organisms than penicillin G, but they have much greater efficacy against G- species.

o Resistance is a growing problem, and therapeutic failures are becoming common.

o Both ampicillin and amoxicillin are available combined with a β-lactamase inhibitor, sulbactam and clavulanic acid, respectively.

o The addition of a β-lactamase inhibitor results in much greater efficacy against G- organisms as well as some β-lactamase– producing gram-positive and anaerobic organisms.

232
Q

What are the antipseudomonal penicillins?

A

Piperacillin and ticarcillin

233
Q

First generation cephalosporines

A

o Cefalexin and cephalosporin

o High level of activity against G+, moderate activity against G-, and minimal activity against anaerobes.

o Used commonly as initial empiric and perioperative therapy because of their spectrum of action and safety profile

234
Q

Second generation cephalosporines

A

o Cefoxitine, cefaclor, cefuroxime, cefotetan

o Stability against β-lactamase.

o Moderately efficacious against G+ and have a greater spectrum of activity against G- than the first-generation cephalosporins.

235
Q

Third generation cephalosporines

A

o Cefotaxime, ceftriaxone, ceftiofur, cefixime, ceftazidime, cefpodoxime, cefovecin

o High degree of specificity for and efficacy against G-.

o Considered the treatment of choice for empiric therapy for infections in the CNS

236
Q

Is MRSA resistant to carbapenems?

A

Yes

237
Q

Carbapenems

A

o The high activity of imipenem is attributed to its stability against most of the β-lactamases (including ESBL) and its ability to penetrate porin channels that usually exclude other drugs.

o Carbapenems are more rapidly bactericidal than the cephalosporins and less likely to induce release of endotoxin in G- sepsis in an animal.

o Meropenem has antibacterial activity approximately equal to or greater than that of imipenem. Is more soluble and can be administered in less fluid volume, more rapidly, and is not as nephrotoxic as imipenem.

238
Q

T/F One of the primary reasons for limiting clinical use of the aminoglycosides is the nephrotoxicity observed with conventional multiple daily dosing

A

TRUE

239
Q

Aminoglycosides MOA

A

o The aminoglycosides are bactericidal agents.

o They penetrate the bacterial cell wall and membrane, and impair protein synthesis by binding to components of the prokaryotic 30s ribosomal subunit.

o This binding leads to bacterial misreading of messenger ribonucleic acid (mRNA), with subsequent production of nonfunctional proteins, detachment of ribosomes from mRNA, and cell death.

240
Q

Aminoglycosides spectrum of activity

A

o Effective against most community-acquired G- aerobes and select G+ pathogens.

o Frequently, although not uniformly, effective against multidrug-resistant Pseudomonas aeruginosa and Escherichia coli.

o Not active against anaerobes because their uptake across bacterial cell membranes depends on energy derived from aerobic metabolism.

o Consequently, they have markedly reduced activity in areas of low pH and oxygen tension (e.g., abscesses)

o Gentamicin is active against many Staphylococcus spp. Other G+ such as Streptococcus spp and many enterococci, are relatively resistant.

o The aminoglycosides are active against some mycobacteria as well as less common pathogens such as Yersinia pestis, Brucella spp, and Francisella tularensis.

241
Q

How are aminoglycosides normally administered?

A

o Aminoglycosides are traditionally administered in combination with another antimicrobial agent to enhance bactericidal activity and minimize resistance.

o In patients with life-threatening infections in which mixed organisms are suspected, aminoglycosides are appropriately administered with a β-lactam, β-lactam/β-lactamase inhibitor, or a carbapenem antibiotic.

o This approach provides not only synergistic bacterial activity but also antibacterial coverage during the aminoglycoside-free interval when single daily dosing is used.

o Metronidazole or clindamycin may be prescribed in combination with an aminoglycoside when coinfection with strict anaerobic pathogens is suspected.

242
Q

Can aminoglycosides be given aerosolized?

A

o Aerosolized gentamicin may be administered to patients with susceptible pulmonary infections with limited risk of systemic absorption and toxicity.

o The effectiveness of inhalational therapy with aminoglycosides has not been studied critically in dogs and cats, although aerosolized gentamicin appears to decrease the clinical signs associated with Bordetella bronchiseptica infection in dogs.

243
Q

Aminoglycosides pharmacology

A

o Patients receiving parenteral aminoglycosides should be well hydrated, have stable renal function, and have an inactive urine sediment.

o The aminoglycosides are highly water soluble and do not readily cross biologic membranes.

o For this reason, they are largely confined to the extracellular fluid and have a correspondingly small volume of distribution (Vd).

o The aminoglycosides are mainly eliminated unchanged in the urine. They are excreted predominately by glomerular filtration, with a small fraction (<5%) undergoing tubular reabsorption.

o Ineffective for treatment of intracellular pathogens.

244
Q

What is adaptive resistance?

A

o Aminoglycosides are associated with a first-exposure effect called adaptive resistance, which is most relevant for G-, including P. aeruginosa.

o This phenomenon is manifested after the first dose by downregulation of aminoglycoside uptake by bacteria following subsequent doses.

o When this occurs, there is less bacterial killing with later doses as well as shorter PAEs.

o Adaptive resistance is most likely to occur with first doses that provide low peak serum concentrations (CMAX).

o Once the first exposure occurs, the downregulation can last for hours. Single daily dosing provides the high serum concentrations necessary to prevent induction of a first-exposure effect, extends the interval between doses to overcome the onset of adaptive resistance, and decreases the incidence of nephrotoxicity.

245
Q

Concentration-dependent bactericidal activity is optimized by attaining a Cmax that exceeds the MIC by a factor of __________

A

o 8 to 10

o The CMAX/MIC ratio is sometimes referred to as the inhibitory quotient.

246
Q

What is the trough level

A

o The lowest concentration in plasma of a drug

247
Q

Aminoglycosides monitoring guidelines

A
248
Q

Nebulized gentamicin

A

o Limited data support the use of aerosolized gentamicin for inhalation as adjunctive therapy in canine patients infected by B. bronchiseptica.

o Injectable gentamicin (6 to 7 mg/kg) diluted 1:2 with sterile saline is placed in the chamber of a jet nebulizer, with each treatment lasting approximately 10 minutes q8-12h.

o Topical delivery is never adequate alone, and systemic antimicrobials must be administered simultaneously.

249
Q

Aminoglycosides toxic effects

A

o Neuromuscular junction, inner ear apparatus, and, most significantly, renal proximal convoluted tubules.

250
Q

Aminoglycosides and neuromuscular junction

A

o Reversible neuromuscular paralysis is uncommon and thought to result from interference with the release and uptake of acetylcholine at the neuromuscular junction.

o They may also inhibit calcium movement into the nerve terminal during depolarization; calcium is required for subsequent release of acetylcholine.

o Weakness may be produced at dosages just slightly higher than those recommended but is likely to be of clinical consequence only in patients with neuromuscular disorders such as myasthenia gravis or those receiving neuromuscular blocking agents.

o Injectable calcium reverses the neuromuscular paralysis produced by aminoglycosides. A cholinesterase inhibitor such as neostigmine also has an antidotal effect.

251
Q

Aminoglycosides and ototoxicity

A

o Can cause both cochlear and vestibular toxicity by accumulating in the affected tissue and destroying sensory hair cells.

o Numerous animal studies in which aminoglycosides were administered by a variety of routes for prolonged periods or at very high dosages, or both, reveal that both dogs and cats are susceptible to irreversible aminoglycoside-induced ototoxicity.

o In the human literature, the incidence of ototoxicity has not been shown to be significantly different with SDD. Rather, the risk of ototoxicity seems to be related to the duration of treatment with aminoglycosides.

252
Q

Aminoglycosides and nephrotoxicity

A

o They cause a nonoliguric renal insufficiency.

o Aminoglycosides damage the cells of the proximal renal tubules and reach maximal tubular toxicity around day 9 of therapy.

o The cationic state of the aminoglycosides facilitates binding to tubular epithelial cells.

o Intracellular transport results in high concentrations of the aminoglycoside within lysosomes → lysosomes eventually destabilize and rupture, which disrupts normal cell structure and function. The resulting decline in glomerular filtration is likely multifactorial in origin and involves both tubular and nontubular mechanisms.

o Clinically, nephrotoxicity generally manifests as polyuric renal failure, with varying degrees of renal dysfunction.

253
Q

Aminoglycosides and nephrotoxicity - 2

A

o Single day dosing is associated with a lower incidence of nephrotoxicity than administration of the same amount of medication in multiple doses.

o In diurnal mammals, glomerular filtration rate is slower at rest (at night). An increased incidence of renal toxicity is observed when the drug is injected during the rest period, and lower toxicity is observed when the aminoglycoside is administered during periods of activity (during the day).

o Examination of the urine sediment for granular or cellular casts on a daily basis is recommended - within 1-2h of collection as casts can dissolve. Also, urine strips to assess for glucosuria and proteinuria.

o Advanced age, duration of therapy, fever, volume depletion, and dehydration increase the risk of aminoglycoside-induced nephrotoxicity. Other risk factors include concomitant administration of nephroactive drugs, preexisting renal disease, and potassium and magnesium depletion.

o Aminoglycosides should not be administered intravenously with solutions containing calcium, sodium bicarbonate, or heparin.

254
Q

T/F Fluoroquinolone antibiotics are entirely synthetic

A

TRUE

255
Q

Fluoroquinolone structure

A

o All quinolone derivatives in clinical use have a dual-ring structure with a nitrogen at position 1, a carbonyl group at position 4, and a carboxyl group attached to the carbon at the 3 position of the first ring.

o Several structural modifications to the original dual ring have resulted in increased potency, extended spectrum, and enhanced bioavailability.

256
Q

FQ’s generations

A

o First-generation drugs (nalidixic acid) achieve minimal serum levels.

Second- generation quinolones (enrofloxacin, difloxacin, marbofloxacin, and ciprofloxacin) have increased G- and systemic activity. Within this class, important differences exist in the rate and extent of biotransformation, rate of elimination, and method of excretion. Approximately 40% of enrofloxacin is metabolized to ciprofloxacin; approximately 40% of marbofloxacin is excreted unchanged by the kidney.

o Third-generation drugs (pradofloxacin) have expanded activity against G+, atypical pathogens, and some anaerobes.

o Fourth-generation fluoroquinolones possess significant activity against G+ and anaerobes.

257
Q

FQ’s MOA

A

o Fluoroquinolone antibiotics exert their antimicrobial effect by inhibiting two enzymes of the topoisomerase class: DNA gyrase (formerly called topoisomerase II), and topoisomerase IV.

o For bacterial replication to proceed, individual strands of bacterial DNA must be separated. This results in “supercoiling,” of DNA strands in front of the replication fork.

o DNA gyrase is a tetramer composed of two A and two B subunits, encoded by the genes gyrA and gyrB, that must function together for supercoiling to proceed.

o Quinolones also inhibit the activity of topoisomerase IV. Topoisomerase IV possesses two C and two E subunits. Topoisomerase IV is capable of removing positive and negative DNA supercoils, but it is primarily responsible for decatenation, or removing the interlinking of daughter chromosomes, which allows segregation into two daughter cells at the end of a round of replication.

o Inhibition of topoisomerase IV is responsible for the bactericidal effect on G+, and DNA gyrase tends to be the primary target for fluoroquinolones in G-.

258
Q

T/F FQ’s differ from other antibiotics such as penicillins, tetracyclines, and macrolides in that they exhibit a high degree of efficacy at relatively low serum concentrations.

A

TRUE

259
Q

FQ’s spectrum

A

o Highly effective against aerobic G-, including most members of the Enterobacteriaceae family (Escherichia coli, Klebsiella), Pasteurella spp, Haemophilus somnus, Bordetella, and Campylobacter, among others.

o Different fluoroquinolones exhibit variable activity against Pseudomonas spp.

o Some of the newer fluoroquinolones are active against G+, including Staphylococcus aureus and Staphylococcus epidermidis.

o Because of their ability to penetrate phagocytic cells, they have activity against many intracellular pathogens, including Mycoplasma, Mycobacteria, Chlamydia, and Brucella.

o However, a study evaluating enrofloxacin for treatment of Mycoplasma haemofelis found that a therapeutic effect was achieved only at levels associated with retinal toxicity.

o Enrofloxacin was not effective in treating Ehrlichia infections in experimentally infected dogs.

o However, pradofloxacin, recently approved for use in small cats in the US, possesses activity against Mycoplasma species as well as intracellular organisms such as Rickettsia spp and Mycobacteria spp.

260
Q

FQ’s PK/PD

A

o Highly bioavailable after both oral and parenteral administration and exhibit excellent tissue distribution.

o They are absorbed rapidly after oral administration, with peak serum levels attainable within 0.5 to 2 hours.

o Administration of oral antacids containing polyvalent cations (magnesium, aluminum, calcium, iron, and zinc) decreases absorption. Food intake does not tend to decrease total serum concentrations of fluoroquinolones, but it may lengthen the time to peak serum concentrations.

o Concentration of quinolone antimicrobials in urine, kidney, lung, prostatic tissue, stool, bile, macrophages and neutrophils often exceeds that in serum.

o Because these agents are concentrated in phagocytic cells, they reach higher concentrations at inflammatory sites.

o Concentration dependent.

o Fluoroquinolones exhibit a marked postantibiotic effect (PAE) in which they continue to inhibit bacterial growth for up to 8 hours after elimination from the body.

261
Q

FQ’s synergy

A

o Typically they are synergistic with antipseudomonal penicillins, ceftazidime, imipenem, and occasionally rifampin and the aminoglycosides.

262
Q

FQ’s resistance

A

o Steady increase in bacterial resistance, particularly among Staphylococcus, Pseudomonas, and E. coli organisms.

o Chromosomal point mutations in the genes encoding DNA gyrase and topoisomerase IV are major mechanisms of quinolone resistance.

o Resistance via decreased drug affinity for the altered enzyme-DNA complex.

o Later generation fluoroquinolone compounds with equal activity against DNA gyrase and topoisomerase IV would require simultaneous mutations in the bacteria at both sites to be rendered ineffective. Double mutants occur rarely, therefore use of these compounds may restrict the development of resistance.

o They can also increase the efflux of the FQ’s (E. coli, Salmonella).

o G- can also regulate membrane permeability by altering the levels of outer membrane porins that form the channels responsible for passive diffusion.

o Recently the emergence of plasmid-mediated fluoroquinolone resistance has been reported.

263
Q

FQ’s are used most frequently to treat infections of the ________, _________, ________, __________ and ________

A

Urinary tract, respiratory tract, skin, GI tract, and bone.

264
Q

What are the bacteria most commonly associated with infections of the urinary tract in the dog?

A

o E. coli, Staphylococcus, Streptococcus, Klebsiella, Proteus, and Pseudomonas.

o A recent study evaluated the efficacy of high-dose, short-duration (HDSD) enrofloxacin (18 to 20 mg/kg orally q24h for 3 days) for the treatment of uncomplicated urinary tract infection in dogs and found HDSD enrofloxacin to be nonin- ferior to a 14-day course of amoxicillin-clavulanate, likely as a result of the high urinary concentration achieved by enrofloxacin.

o Enrofloxacin reaches higher concentrations in prostatic tissue than in serum and is therefore very effective against susceptible organisms causing bacterial prostatitis in the dog.

265
Q

Adverse effects of rapid intravenous administration of FQ’s may include __________ and _________ ___________.

A

seizures and neurologic sequelae.

266
Q

T/F - Some fluoroquinolones inhibit P-450 metabolism and may slow down the metabolism of theophylline and aminophylline, leading to toxicity from elevated levels of methylxanthines.

A

o TRUE

o FQ’s may decrease the effectiveness of concurrently administered phenytoin.

o The use of FQ’s and warfarin concomitantly may result in excessive anticoagulation.

267
Q

FQ’s adverse effects

A

o V/D/N, and abdominal discomfort → these effects are typically mild and dosage related.

o Seizures, tremors

o They directly inhibit γ-aminobutyric acid receptors and stimulate N-methyl-d-aspartate receptors in the central nervous system.

o They have been associated with cartilaginous defects in juvenile animals and humans.

o The pathogenesis of quinolone-induced cartilage damage is multifactorial. Proposed mechanisms include inhibition of proteoglycan synthesis, chelation of magnesium, and inhibition of mitochondrial dehydrogenase activity.

o In humans, the damage appears to be reversible with discontinuation of therapy.

o In one veterinary study, cartilage defects in young dogs were exacerbated by exercise and prevented by exercise restriction.

o Use of fluoroquinolone antibiotics is contraindicated in young, growing dogs between the ages of 2 and 8 months and up to 18 months in large breed dogs.

o Irreversible blindness in cats - suspected due to high dose rather than idiosyncratic effect → retinal degeneration.

268
Q

T/F - Macrolides represent a large group of similar compounds that are all products of Streptomyces spp

A

TRUE

269
Q

Macrolides with the greatest clinical efficacy generally are derived from _________

A

Erythromycin

270
Q

Macrolides MOA

A

o All macrolides work by reversibly binding the 50s ribosome.

o This results in suppression of ribonucleic acid–dependent protein synthesis.

o Macrolides are bacteriostatic at clinical concentrations.

271
Q

Macrolides spectrum

A

o They are particularly effective against G+ and Mycoplasma spp.

o They have fair efficacy against anaerobic organisms.

o Azithromycine has efficacy against some G-.

o Many macrolides are actively concentrated in macrophages → can result in very high drug concentrations at the site of infection.

272
Q

Macrolides PK/PD

A

o Low serum concentrations and large volumes of distribution.

o Concentrated in tissues including the lung, heart, and macrophages.

o Newer macrolides such as azithromycin have high oral bioavailability (40% to 60%) and long half-lives.

o The main route of excretion is through bile and the intestinal tract.

273
Q

Macrolides resistance

A

o Can develop rather quickly.

o Through a one-step mutation that confers high levels of resistance.

This type of resistance can be unstable, but it can develop during treatment.

o Caused by an efflux pump that actively excretes the drug out of the cell.

274
Q

T/F Erythromycin PO is subject to rapid degradation by gastric acid.

A

TRUE

o Tablets and capsules typically are protected by an enteric coating. It is important that tablets not be crushed or divided because this can result in inactivation of the drug before it is absorbed.

275
Q

In which conditions is typically used erythromycin?

A

In those with liver failure for its prokinetic effects on GI smooth muscle and its ability to limit overgrowth of ammonia- producing organisms within the GI tract.

276
Q

Azithromycin

A

o It is more stable in acid and as a result has a high oral bioavailability compared to erythromycin.

o Tissue concentrations are generally 10 to 100 times those achieved in serum, and the drug can be concentrated 200 to 500 times in macrophages.

o This high level of drug in macrophages may not always be advantageous because it can suppress phagocytic activity.

o Does not exhibit any effect on GI smooth muscle → GI adverse effects are uncommon.

o Care should be taken when using azithromycin as the sole agent because of the limitations in its G- spectrum and because resistance is a growing problem.

o Should be reserved for use as a second-line or third-line agent.

277
Q

Metronidazole spectrum

A

o Has clinical activity against anaerobic G- bacilli (e.g., Bacteroides spp), anaerobic G+ bacilli (e.g., Clostridium spp) anaerobic G+ cocci (e.g., Peptostreptococcus spp), and some protozoa (e.g., Giardia)

o It does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes.

278
Q

Metronidazole MOA

A

o The nitro group is reduced, and the reduction products appear to be responsible for the antimicrobial effects of metronidazole, which include disruption of DNA and inhibition of nucleic acid synthesis.

o Mammalian cells are unharmed because they lack enzymes to reduce the nitro group of these agents.

o The beneficial effects of metronidazole are often attributed to its antiinflammatory proper- ties, in addition to its antibacterial activity.

o The immunomodulatory effects of metronidazole may be partly responsible for amelioration of clinical signs with inflammatory enteropathies and gingivostomatitis.

279
Q

Metronidazole PK/PD

A

o Metronidazole diffuses well into tissues and body fluids, including cerebrospinal fluid, bile, and abscesses.

280
Q

Metronidazole adverse effects

A

o Seizures, cerebellar dysfunction, and other neuropathies have been reported with high dosages or long-term use of metronidazole.

o These effects are generally self-limiting, complete recovery may take days to weeks.

o Dosage should not exceed 20 to 30 mg/kg q24h for dogs and cats, generally divided into twice-a-day dosing.

o Metronidazole should be used with particular caution in patients with underlying neurologic disorders.

o Intravenous diazepam administration may lessen the duration and severity of neurologic signs in affected dogs. Patients with severe hepatic disease metabolize metronidazole slowly; therefore 15 to 20 mg/kg q24h is administered in such circumstances.

281
Q

Chloramphenicol MOA

A

o It acts primarily on the 50s ribosomal subunit and suppresses the activity of peptidyl transferase, an enzyme that catalyzes peptide bond formation.

o Depending on the pathogen, the effect of CHPC may be bactericidal or bacteriostatic.

282
Q

Chloramphenicol spectrum

A

o CHPC is active against G+ and G- aerobic and anaerobic bacteria, as well as spirochetes, rickettsiae, chlamydiae, Bordetella, and Mycoplasma spp.

o It is often effective for treating Salmonella and Escherichia infections in the gastrointestinal (GI) tract.

o Its spectrum of activity generally does not include Pseudomonas aeruginosa.

o CHPC is not predictably active against most Ehrlichia spp.

o Although its lipid solubility permits it to cross the blood-brain barrier, its effectiveness for treating central nervous system (CNS) infections is unpredictable.

283
Q

Chloramphenicol PK/PD

A

o Metabolism takes place mainly in the liver, and inactive conjugated CHPC is excreted by the kidneys.

o Although only a small fraction of active CHPC appears unchanged in the urine, adequate concentrations are achieved to treat many urinary tract infections (in the absence of advanced renal disease).

o CHPC is a cytochrome P-450 inhibitor and thus may decrease the clearance of other drugs that are metabolized by the same enzymes.

o CHPC may inhibit the metabolism of drugs such as opiates, barbiturates, and propofol.

284
Q

Chloramphenicol adverse effects

A

o Reversible bone marrow suppression and GI upset with high doses.

o Hind limb weakness and tremors associated with CHPC administration are reported in large breed dogs.

o Ataxia, paresis, and pelvic limb dysfunction are seen in some dogs and reportedly resolve with drug discontinuation or dose reduction.

o CHPC exposure through aerosolization or oral intake is associated with fatal bone marrow aplasia in humans.

285
Q

What drugs include the tetracycline class?

A

Doxycycline, tetracycline, oxytetracycline and minocycline.

286
Q

Tetracyclines MOA

A

o Generally considered bacteriostatic.

o They bind primarily to the 30s subunits of bacterial ribosomes and inhibit protein synthesis.

o As with other tetracyclines, doxycycline possesses a number of nonantibacterial effects including antiinflammation, immunomodulation, inhibition of collagenase activity, and wound healing.

287
Q

Tetracyclines PK/PD

A

o Doxycycline is the only tetracycline recommended for intravenous use in SA.

o Doxycycline is highly lipophilic and has excellent tissue penetration including prostate, bile, lung and bronchial secretions.

o Drug concentrations measured in most tissues are generally higher than those in serum.

288
Q

Tetracyclines spectrum

A

o Has a broad spectrum of activity against many G+, G-, aerobic, and anaerobic bacteria, including Mycoplasma spp, chlamydiae, rickettsiae, spirochetes, and select mycobacteria.

o It is the drug of choice for treating Lyme disease, brucellosis, and most Ehrlichia infections in dogs.

o It is very effective against many strains of Bordetella bronchiseptica. Hemotropic mycoplasmosis and infections with Bartonella spp may be treated with high-dosage doxycycline.

o It is often a first-line treatment for respiratory infections, especially those caused by Bordetella bronchiseptica.

o Intravenous doxycycline is used for life-threatening infections with Borrelia burgdorferi and Leptospira spp. Doxycycline is effective for both active bacteremia and the elimination of leptospires from tissues.

289
Q

Tetracylines adverse effects

A

o Most adverse effects → oral administration → GI upset and pill-induced esophageal erosion, particularly in cats.

o The incidence of esophageal damage may be decreased by using coated or liquid forms of the drug and providing at least 10 ml of water or gruel to the patient immediately after, while maintaining the patient in an upright position to ensure that the medication passes into the stomach.

o Teeth discoloration seen with tetracycline but not with doxycycline.

o Drugs in the tetracycline family should never be administered after the medication’s expiration date. Ingredients used in the manufacture of these medicines break down over time to form toxins that are particularly damaging to the kidneys.

290
Q

What antibiotics are in the potentiated sulfonamide class?

A

Sulfonamide antibiotics such as sulfamethoxazole (SMX), sulfadiazine (SDZ), and sulfadimethoxine (SDM), potentiated by combination with either trimethoprim (TMP) or orme- toprim (OMP).

291
Q

Sulfonamides MOA

A

o Inhibit two consecutive steps in bacterial folic acid synthesis.

o Folate is necessary for cells to synthesize nucleic acids, and in its absence cells are unable to divide.

o Folate is not synthesized in mammalian cells but is instead a dietary requirement. This explains the selective toxicity of these agents to bacterial cells.

292
Q

Sulfonamides spectrum

A

o They are considered bactericidal against facultative G- bacteria and staphylococci.

o They have unpredictable activity against streptococci and no activity against enterococci or obligate anaerobes.

o Many strains of S. aureus, Escherichia coli, Proteus mirabilis, Enterobacter spp, and Salmonella enterica are inhibited by the parenteral combination of TMP-SMX.

o TMP-SMX is considered a first-line agent for nocardial infections.

o TMP-SMX generally not effective for Bacteroides, Serratia, Klebsiella, or Enterococcus spp.

293
Q

Sulfonamides adverse effects

A

o Anemia, proteinuria, crystalluria, and hematuria, as well as inhibition of thyroid hormone synthesis.

o Effects on thyroid hormone function are most likely to manifest after 2 to 3 weeks of therapy and are reversible.

o Delayed hypersensitivities.

o Larger dogs appear to be predisposed to sulfonamide-associated polyarthropathy.

o Sulfonamide- induced KCS is distinct from other adverse events in that the time to onset of signs is often months to years, rather than days to weeks. Incidence of about 15%. Reversible → monitor Schirmers test.

294
Q

Vancomycin MOA

A

o It works by binding to peptide precursors in the bacterial cell wall, preventing cross-linking of peptidoglycan side chains and thereby inhibiting cell wall synthesis.

295
Q

Vancomycin spectrum

A

o Limited to most aerobic and anaerobic G+ organisms, including most isolates resistant to β-lactams.

o Vancomycin use has increased and it remains the main agent for β-lactam–resistant staphylococcal and enterococcal infections in most human hospitals. It is a drug of last resort in veterinary medicine.

296
Q

Vancomycin PK/PD

A

o Not absorbed across the intestinal wall, and its use is therefore limited to parenteral administration for all infections other than Clostridium difficile–associated diarrhea.

o Clinically useful concentrations are achieved in heart, lung, kidney, synovium, and the peritoneal cavity.

o May not reach therapeutic levels in pleural fluid and bile, although it has been used for treating bacterial cholangiohepatitis in cats.

o Vancomycin is eliminated almost exclusively by the kidney, and dosage is adjusted in human patients with renal dysfunction.

o Vancomycin-associated renal impairment is reported, although it is infrequent and generally mild. However, vancomycin may potentiate aminoglycoside nephrotoxicity.

297
Q

Polymyxins

A

o Polymyxins B and E (E, aka colisitin) have a broad spectrum of activity that includes many G- bacteria.

o They are cationic detergents that interact with the phospholipids of bacterial cell membranes, which leads to increased cell wall permeability and cell death.

o In addition to their bactercidal properties, polymyxins can bind and neutralize lipopolysaccharide and prevent the pathophysiologic effects of endotoxin in circulation.

298
Q

Polymyxin E (colistin) spectrum

A

o Shows bactericidal activity against most strains of Enterobacter aerogenes, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae.

o It has no activity against Proteus spp, Serratia spp, G+ cocci, or anaerobes.

o Used for infections with MDR G- bacteria or by the inhalational route in select patients with pneumonia due to panresistant strains of Pseudomonas aeruginosa.

299
Q

Clindamycin MOA and PK/PD

A

o Binds to the 50s ribosomal subunit and inhibits protein synthesis in susceptible bacteria.

o Clindamycin is lipophilic and widely distributed in body tissues and fluids, including bile, prostatic fluid, and bone.

o Importantly, clindamycin accumulates in walled-off abscesses, surpassing concentrations of CHPC and penicillins.

o Although clindamycin achieves very high concentrations in phagocytic leukocytes, it does not have enhanced activity against obligate intracellular pathogens; this is likely because the subcellular location of the antibiotic does not match that of the organism.

300
Q

Clindamycin spectrum

A

o It shares the G+ coccal spectrum of erythromycin but is more active against susceptible staphylococci, including some methicillin-resistant isolates, as well as Toxoplasma gondii, Neospora caninum, Hepatozoon, and Babesia spp.

o Clindamycin is the treatment of choice for toxoplasmosis in dogs and cats.

o Because it has no clinically significant activity against facultative G- enteric bacteria, clindamycin is appropriately prescribed with an antimicrobial with enhanced G- coverage when treating polymicrobic infections.

o Despite increasing resistance, clindamycin remains one of the drugs of choice for most anaerobic infections.

o It may be preferred over CHPC and metronidazole because of less toxicity.

301
Q

What is inducible resistance to clindamycin?

A

o Inducible resistance to clindamycin (ICR) is a phenomenon in which the gene for resistance to clindamycin is not expressed until exposure to the antibiotic.

o There is potential for clinical failure when patients infected with strains of staphylococci with ICR are treated with clindamycin.

o ICR may be suspected when the organism demonstrates in vitro resistance to erythromycin and susceptibility to clindamycin.

302
Q

Clinical uses of clindamycin

A

o It is recommended for use in a variety of skin, soft tissue, and respiratory infections. It is widely used for post-surgical orthopedic infections.

o When clindamycin is administered at recommended dosages, adverse events are infrequent in dogs and cats. Clindamycin may cause anorexia, vomiting, and diarrhea with higher doses.

303
Q

Rifampin

A

o Acts by blocking RNA polymerase.

o It is active against many G- and most G+ bacteria.

o Rifampin is the most active antibiotic against Staphylococci

o It is active against most strains of MRSP.

o Resistance develops rapidly with rifampin monotherapy → limited by combining rifampin with another antibiotic to which the organism is susceptible.

o Rifampin is potentially hepatotoxic. Mild elevations in ALP are common (no concern). Increases in other liver enzymes → stop → hepatotoxicity and acute hepatitis are occasionally reported → not to exceed 10mg/kg q24h.

o Anorexia and vomiting may also occur. Hemolytic anemia and thrombocytopenia are rare.

o Rifampin may produce reversible discoloration (orange tint) of urine, tears, and saliva.

304
Q

Newer agents against MDR G+ cocci

A

Daptomycin

Tigecycline

Quinupristin-Dalfopristin

Linezolid

305
Q

Daptomycin

A

o Bactericidal against a range of G+ isolates. MRSA and vancomycin- resistant Enterococcus faecium (VREF).

o MOA is thought to disrupt plasma membrane function, which leads to the release of intracellular ions, specifically potassium, and results in cell death.

o Concentration dependent.

o It is used primarily for skin and soft tissue infections caused by G+ bacteria but is also used for complicated urinary tract infections. It is inactivated by surfactant and is not useful for treating pneumonia.

o It is a relatively safe drug with very few reported adverse effects.

o Daptomycin has limited hepatic metabolism, is eliminated primarily by the kidneys → dosage adjustments in patients with renal dysfunction.

306
Q

Tigecycline

A

o Novel tetracyclines with G+ and G- activity.

o MOA is similar to that of tetracycline, but it has improved ability to circumvent resistance.

o It is one of the newest approved agents with activity against MDR G+ pathogens.

o It is used to treat complicated soft tissue and intraabdominal infections in humans.

o Active against some resistant Enterococcus strains and MRSA, as well as certain β-lactamase–producing Enterobacteriaceae and anaerobes.

o It is available only for parenteral administration.

307
Q

Quinupristin-Dalfopristin

A

o Is a combination of two semisynthetic streptogramin drugs where both have antibacterial capability individually, but they demonstrate synergistic activity when used in combination.

o Both enter bacterial cells by diffusion and bind to different sites on ribosomes, which results in irreversible inhibition of bacterial protein synthesis. Eliminated through the bile into feces.

o Active against a broad spectrum of G+ bacteria, including MRSA, VREF, and many streptococci. Has shown synergy with other antibiotics → in vitro with rifampin against MRSA and with doxycycline against VREF.

o Indicated for the treatment of serious infections caused by MDR organisms, VREF, and MRSA, including soft tissue infections, pneumonia, and bacteremia.

o It is administered intravenously. Adverse events are reported infrequently but include myalgia, discomfort or thrombophlebitis at the site of injection, nausea, and increases in hepatic transaminase activity.

o Although uncommon, resistance to quinupristin-dalfopristin has been encountered among VREF and MRSA in the United States.

308
Q

Linezolid

A

o It is thought to inhibit the initiation phase of translation and thus interfere with protein synthesis.

o In vitro studies → effective against many antibiotic-resistant G+ organisms, including MRSA and VRE.

o It is effective against G- anaerobes, including Bacteroides fragilis and some mycobacteria.

o Linezolid has been approved in humans for the treatment of various G+ infections like pneumonia, skin infections, and soft tissue infections.

o Available IV and PO.

o Resistance has been documented in both enterococci and staphylococci, which may limit the use of this drug in the near future.

o Human patients uncommonly experience adverse events such as nausea and self-limiting thrombocytopenia. Less common, but more serious adverse effects include severe lactic acidosis and a disabling polyneuropathy.

309
Q

Suggested empirical antibiotic treatment based on site of infection

A
310
Q

T/F It is not always necessary to perform gram staining. Most cocci are gram positive and most important bacilli are gram negative.

A

TRUE

311
Q

If the organism is a G+ coccus, one should assume that it is a _______ or _________. If it is a G- bacillus, one should assume that it is __________

A

Streptococci

  • Staphylococcus,* most likely S. pseudintermedius.
  • E. coli.*
312
Q

Empirical antibiotic selection for critically ill based on morphology and gram stain

A
313
Q

T/F Staphylococcus isolated from small animals is most likely to be S. pseudintermedius rather than S. aureus.

A

TRUE

o Although methicillin resistance is a growing concern, it should initially be assumed that this is a wild-type strain and susceptible to antistaphylococcal agents. These staphylococci usually have predictable susceptibility to β-lactam antibiotics, such as amoxicillin-clavulanic acid or ampicillin-sulbactam.

314
Q

T/F If a blood-borne pathogen is suspected (e.g., Hemoplasma spp, Rickettsia spp, or Ehrlichia canis), initial treatment almost always consists of doxycycline.

A

TRUE

315
Q

Antibiotic selection when first treatment has failed and resistance is suspected

A
316
Q

What is perfusion rate–limited drug diffusion

A

Diffusion of most antibiotics from plasma to tissues is limited by tissue blood flow, rather than drug lipid solubility.

317
Q

What is permeability rate–limited drug diffusion.

A

o When in some tissues a lipid membrane (e.g., tight junctions on capillaries) presents a barrier to drug diffusion.

o A drug must be sufficiently lipid soluble or be actively carried across the membrane to reach effective concentrations in tissues. These tissues include the central nervous system, eye, and prostate. A functional membrane pump (P-glycoprotein) also contributes to the barrier.

318
Q

T/F Hydrophilic drugs may be more likely to diffuse through the blood-bronchus barrier and reach effective drug concentrations in bronchial secretions.

A

FALSE - lipophilic drugs

319
Q

Urine concentrations of antibiotics may be at least _____ times the corresponding plasma concentrations because of the tubular concentration.

A

100

When the renal tissue is involved, high urine drug concentrations offer no advantage.

320
Q

T/F Drug concentrations in renal tissue—which are equivalent to the renal lymph concentrations—are correlated with plasma drug concentrations, not with the drug concentrations in the urine.

A

TRUE

321
Q

Examples of drugs that accumulate in leukocytes, fibroblasts, macrophages, and other cells

A

o Fluoroquinolones.

o Lincosamides (clindamycin, lincomycin).

o Tetracyclines (doxycycline, minocycline)

o Macrolides (erythromycin, clarithromycin, azithromycin)

322
Q

Examples of local tissue factors that may decrease antimicrobial effectiveness

A

o Pus and necrotic debris may bind and inactivate vancomycin or aminoglycoside or decrease the activity of topical agents such as polymyxin B.

o Foreign material in a wound (such as surgically implanted material) can protect bacteria from antibiotics and phagocytosis by allowing them to form a biofilm (glycocalyx) at the site of infection.

o Cellular debris and infected tissue can inhibit the action of trimethoprim-sulfonamide com- binations through the secretion of thymidine and p-aminobenzoicacid → inhibitors of these drugs.

o Cations can adversely affect the activity of antimicrobials at the site of infection. Two important drug groups diminished in activity by cations such as Mg2+, Al+3, Fe+3, and Ca2+ are fluoroquinolones and aminoglycosides.

o An acidic environment of infected tissue may decrease the effectiveness of clindamycin, macrolides (e.g., erythromycin, azithromycin), fluoroquinolones, and aminoglycosides.

o Penicillin and tetracycline activity is not affected as much by tissue pH, but hemoglobin at the site of infection decreases the activity of these drugs.

o An anaerobic environment decreases the effectiveness of aminoglycosides because oxygen is necessary for drug penetration into bacteria.

o Effective antibacterial drug concentrations may not be attained in tissues that are poorly vascularized (extremities during shock, sequestered bone fragments, and endocardial valves).

323
Q

T/F Drugs traditionally considered bactericidal can be bacteriostatic if the concentrations are low. Drugs traditionally considered bacteriostatic can be bactericidal against some bacteria and under optimum conditions

A

TRUE