Pharmacology

Question 1

Applications of benzodiazepines in critically ill

Answer 1

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

Question 2

Are benzodiazepines scheduled substances?

Answer 2

Yes, class IV

Question 3

MOA of benzodiazepines

Answer 3

• 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

Question 4

Diazepam vs midazolam - differences

Answer 4

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.

Question 5

Does benzodiazepines have always sedative effects?

Answer 5

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.

Question 6

Complication of oral diazepam in cats

Answer 6

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

Question 7

Which one is shorter acting, diazepam or midazolam

Answer 7

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

Question 8

How can we reverse benzodiazepines?

Answer 8

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

Question 9

Indications for flumazenil
Doses

Answer 9

• 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

Question 10

Benzos as anticonvulsant therapy
Doses for sedation / anticonvulsant

Answer 10

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

Question 11

Benzodiazepines and appetite stimulant

Answer 11

• 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.

Question 12

Hepatic encephalopathy and benzos

Answer 12

• 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.

Question 13

Percentage of cases reporting to veterinary referral centers involving epilepsy

Answer 13

0.6% to 2.3%

Question 14

Age of idiopathic epilepsy

Answer 14

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

Question 15

Idiopathic epilepsy incidence

Answer 15

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

Question 16

Most common anticonvulsants

Answer 16

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.

Question 17

Phenobarbital MOA and metabolism

Answer 17

• 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

Question 18

How long does it takes to achieve therapeutic levels of phenobarbital

Answer 18

15 to 20 minutes with phenobarbital IV

Question 19

Clinical response to phenobarbital

Answer 19

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

Question 20

Phenobarbital doses in cats

Answer 20

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

Question 21

Loading doses of phenobarbital

Answer 21

• 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.

Question 22

Serum phenobarbital levels that has risk of hepatotoxicity?

Answer 22

>40mcg/mL

Question 23

Half-life of phenobarbital

Answer 23

• 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

Question 24

Phenobarbital monitoring

Answer 24

• 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.

Question 25

Phenobarbital adverse effects

Answer 25

• 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

Question 26

Bloodwork changes with phenobarbital

Answer 26

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

Question 27

Anticonvulsant drugs and recommended dosages for dogs

Answer 27

Question 28

Bromide MOA

Answer 28

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

Question 29

Bromide metabolism

Answer 29

• 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

Question 30

Clinical efficacy of KBr

Answer 30

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

Question 31

Why is not KBr recommended in cats

Answer 31

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

Question 32

KBr doses

Answer 32

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

Question 33

KBr therapeutic range

Answer 33

• 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.

Question 34

KBr adverse effects

Answer 34

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

Question 35

What is bromism / clinical signs / treatment

Answer 35

• 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

Question 36

Zonisamide class and MOA

Answer 36

• 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

Question 37

Zonisamide metabolism

Answer 37

• 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

Question 38

Zonisamide clinical efficacy

Answer 38

• 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

Question 39

Zonisamide doses and therapeutic range

Answer 39

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

Question 40

Zonisamide adverse effects

Answer 40

• 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

Question 41

Zonisamide monitoring

Answer 41

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

Question 42

Levetiracetam MOA

Answer 42

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

Question 43

Levetiracetam metabolism

Answer 43

• 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

Question 44

Levetiracetam doses and therapeutic range

Answer 44

• 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

Question 45

Levetiracetam adverse effects

Answer 45

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

Question 46

Levetiracetam monitoring

Answer 46

• 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.

Question 47

Gabapentin and pregabalin MOA

Answer 47

• 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.

Question 48

Gaba and pregabalin metabolism

Answer 48

• 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.

Question 49

Gaba and pregabalin clinical efficacy

Answer 49

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

Question 50

Gaba and pregabalin doses and therapeutic range

Answer 50

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

Question 51

Gabapentin and pregabalin adverse effects

Answer 51

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

Question 52

Is Felbamate used commonly in veterinary medicine?

Answer 52

No, it has fallen out of favor

Question 53

Felbamate MOA

Answer 53

• Inhibition of aspartate receptor-mediated excitation
• Potentiation of GABAergic activity

Question 54

Felbamate metabolism

Answer 54

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

Question 55

Felbamate doses and therapeutic range

Answer 55

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

Question 56

Felbamate adverse effects

Answer 56

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

Question 57

What’s the mechanism of action of azathioprine

Answer 57

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.

Question 58

What’s the mechanism of action of cyclosporine

Answer 58

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.

Question 59

What’s the mechanism of action of Mycophenolate Mofetil

Answer 59

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

Question 60

What’s the mechanism of action of Leflunomide

Answer 60

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.

Question 61

What’s the mechanism of action of IVIG

Answer 61

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

Question 62

Actions of anticholinergics

Answer 62

• 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

Question 63

Pharmacokinetics - what is and stages

Answer 63

It is how the drug moves through the body

Absorption

Distribution

Metabolism

Excretion

Question 64

Name routes of medication administration

Answer 64

• PO
• Rectal
• Topical
• Intradermal
• SQ
• IM
• IV
• Inhaled
• Buccal
• Sublingual

Question 65

Name mechanisms of drug absorption

Answer 65

• 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.

Question 66

How does pH affect weak acid drugs absorption?

Answer 66

• 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.

Question 67

How does pH affect weak base drugs absorption?

Answer 67

• 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.

Question 68

How can blood flow affect drug absorption

Answer 68

• 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

Question 69

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

Answer 69

• 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.

Question 70

How can p-glycoprotein affect drug absorption?

Answer 70

• 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.

Question 71

What is bioavailability?

Answer 71

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

Question 72

How do we calculate bioavailability (F)?

Answer 72

F = AUC oral / AUC IV

Question 73

What factors affect bioavailability?

Answer 73

• Solubility
• Instability
• First pass effect

Question 74

How can solubility affect bioavailability?

Answer 74

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

Question 75

How can instability affect bioavailability

Answer 75

• 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.

Question 76

How can the first pass effect can affect bioavailability?

Answer 76

• 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.

Question 77

What is the pKa of a drug?

Answer 77

• The degree of ionization (pK_a) of a drug is a unique physicochemical property that controls its ionization state when in solution.
• If the drug’s pK_a 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.

Question 78

What is the distribution process and what factors affect it?

Answer 78

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

Question 79

How does blood flow affects drug distribution?

Answer 79

• 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

Question 80

How does capillary permeability affect drug distribution?

Answer 80

• 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.

Question 81

How does protein binging affects drug distribution?

Answer 81

• 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.

Question 82

How will solubility affect drug distribution?

Answer 82

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

Question 83

What is the volume of distribution (Vd)?

Answer 83

• 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.

Question 84

Low volume distribution drug example

Answer 84

• 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.

Question 85

Intermediate volume distribution drug example

Answer 85

• 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

Question 86

High volume distribution drug example

Answer 86

• 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.

Question 87

How can we calculate Vd?

Answer 87

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.

Question 88

What can the liver do to drugs / toxins?

Answer 88

• 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

Question 89

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

Answer 89

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.

Question 90

Phase I of biotransformation

Answer 90

• 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.

Question 91

What factors can affect phase I of biotransformation?

Answer 91

• 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.

Question 92

Phase II biotransformation

Answer 92

• 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.

Question 93

Factors that affect drug distribution

Answer 93

Question 94

What factors affect oral bioavailability?

Answer 94

Question 95

How can sepsis affect Vd?

Answer 95

Question 96

What is clearance of a drug?

Answer 96

What comes in vs what comes out of a drug

Question 97

What is the extraction ratio (E)?

Answer 97

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

Question 98

How can sepsis alter clearance?

Answer 98

Question 99

What is the elimination of a drug?

Answer 99

• 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

Question 100

How can sepsis affect the pharmacokinetics of medications?

Answer 100

Question 101

Define drug absorption

Answer 101

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

Question 102

Define bioavailability (F%)

Answer 102

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

Question 103

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

Answer 103

AUC

Question 104

Define drug distribution

Answer 104

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

Question 105

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

Answer 105

FALSE - most are lipophilic with a large Vd

Question 106

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

Answer 106

does not

Question 107

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

Answer 107

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

Question 108

List hydrophilic antibiotics

Answer 108

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

Question 109

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.

Answer 109

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

Question 110

List lipophilic antibiotics

Answer 110

Macrolides
fluoroquinolones
Lincosamides

Question 111

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?

Answer 111

the drug that is 30% protein bound

Low protein binding = increased vD

Question 112

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

Answer 112

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

Question 113

Dose/AUC = ????

Answer 113

Clearance

Question 114

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

Answer 114

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

Question 115

A drug takes ____ half lifes to reach steady state

Answer 115

3 to 5

Question 116

Inhibitors of CYP450

Answer 116

Ketoconazole

Omeprazole

Cimetidine

Fluoxetine

Fluoroquinolones

Question 117

Inducers of CYP450

Answer 117

Phenobarbital

Rifampin

Glucocorticoids

Omeprazole

Question 118

What is the usefulness of half life

Answer 118

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

Question 119

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

Answer 119

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

Question 120

What is the steady state of a drug?

Answer 120

The rate going in equals the rate going out

Question 121

What is the first pass metabolism?

Answer 121

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.

Question 122

What are the 2 principal factors that affect pK?

Answer 122

Volume of distribution

Drug clearance

Question 123

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

Answer 123

TRUE

Question 124

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.

Answer 124

TRUE

Question 125

Is Vd increased or decreased in critically ill?

Answer 125

Increased

Question 126

Why is Vd increased in critical illness?

Answer 126

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.

Question 127

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

Answer 127

Increased

Question 128

What happens when the patient starts recovering with the Vd?

Answer 128

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.

Question 129

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

Answer 129

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

Question 130

What is augmented renal clearance (ARC)?

Answer 130

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.

Question 131

When is augmented renal clearance most typically seen?

Answer 131

o In critically ill patients with normal serum creatinine concentrations

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

Question 132

What is minimum inhibitory concentration (MIC)?

Answer 132

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

Question 133

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

Answer 133

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

Question 134

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

Answer 134

Higher

Question 135

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.

Answer 135

4-8

Question 136

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

Answer 136

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.

Question 137

What are time-dependent antibiotics?

Answer 137

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.

Question 138

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

Answer 138

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

Question 139

What is a concentration-dependent antibiotic?

Answer 139

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.

Question 140

What are the 3 pillars of effective antimicrobial therapy?

Answer 140

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)

Question 141

What are the main goals of antimicrobial therapy?

Answer 141

o Rapidly reduce the microbial load

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

Question 142

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.

Answer 142

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%.

Question 143

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

Answer 143

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.

Question 144

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.

Answer 144

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.

Question 145

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

Answer 145

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).

Question 146

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

Answer 146

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

Question 147

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

Answer 147

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

Question 148

Why combination therapy of antibiotics is recommended in CI patients?

Answer 148

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.

Question 149

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

Answer 149

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.

Question 150

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

Answer 150

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.

Question 151

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.

Answer 151

TRUE

Question 152

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

Answer 152

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.

Question 153

What is therapeutic drug monitoring?

Answer 153

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.

Question 154

What does therapeutic drug monitoring (TDM) normally measures?

Answer 154

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.

Question 155

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

Answer 155

Longer

Question 156

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

Answer 156

Short

Question 157

What is antimicrobial resistance?

Answer 157

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

Question 158

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

Answer 158

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.

Question 159

What types of resistance can bacteria exhibit?

Answer 159

o Three: intrinsic, circumstantial and acquired.

Question 160

What is intrinsic resistance of a bacteria?

Answer 160

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.

Question 161

What is circumstantial resistance?

Answer 161

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)

Question 162

What is acquired resistance?

Answer 162

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.

Question 163

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

Answer 163

Acquired

Question 164

Define multidrug resistant (MDR) organism

Answer 164

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

Question 165

What is an extensively drug resistant (XDR) organism?

Answer 165

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

Question 166

What is a pan drug resistant organism (PDR)?

Answer 166

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

Question 167

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

Answer 167

Microdilution test

Question 168

What is the minimum bactericidal concentration (MBC)?

Answer 168

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

Question 169

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

Answer 169

On the breakpoint concentration for that specific bacterium.

Question 170

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

Answer 170

Less

Susceptible

Question 171

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

Answer 171

Greater

Resistant

Question 172

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

Answer 172

TRUE

Question 173

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

Answer 173

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.

Question 174

What would be the ideal antibiotic in critically ill?

Answer 174

o Minimal side effects

o Can be given IV

o Is bactericidal.

Question 175

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

Answer 175

Lower

Question 176

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

Answer 176

To have a Cmax / MIC ratio of >10

Question 177

Example of synergistic effect with antimicrobials?

Answer 177

o B-lactams + aminoglycosides

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

Question 178

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

Answer 178

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.

Question 179

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

Answer 179

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.

Question 180

Should we use antibiotics labeled as resistant

Answer 180

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.

Question 181

Spectrum of ampicillin + sulbactam

Answer 181

G+, G- and anaerobes

Question 182

What is the spectrum of enrofloxacin?

Answer 182

G-

Question 183

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

Answer 183

TRUE

Question 184

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

Answer 184

TRUE

Question 185

Cephalosporin comparsion

Answer 185

Question 186

What is the peak concentration over MIC?

Answer 186

The highest concentration reached with a concentration dependent antibiotic

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

Question 187

Bactericidal vs bacteriostatic antibiotics

Answer 187

Question 188

What is cilastatin?

Answer 188

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

Question 189

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

Answer 189

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.

Question 190

With which number of CFU should we suspect resistance?

Answer 190

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

Question 191

Name common resistant organisms

Answer 191

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

Question 192

Define nosocomial infection

Answer 192

Infections arising more than 48h after hospital admission.

Question 193

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

Answer 193

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.

Question 194

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

Answer 194

TRUE

Question 195

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

Answer 195

G- aerobes

G- aerobes

Anaerobes

Question 196

When should we consider anaerobic coverage?

Answer 196

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)

Question 197

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

Answer 197

G- aerobes

Question 198

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

Answer 198

TRUE

(Pseudomonas aeruginosa, Enterococcus spp. and MRSA)

Question 199

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

Answer 199

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

Question 200

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

Answer 200

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)

Question 201

How many levels of drug penetration exist in normal tissues?

Answer 201

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.

Question 202

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

Answer 202

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.

Question 203

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

Answer 203

2-30%

30-80%

Question 204

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

Answer 204

Decrease

Question 205

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

Answer 205

Septic shock and trauma

Question 206

How should we monitor for aminoglycosides drug concentration?

Answer 206

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

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

Question 207

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

Answer 207

Decreased

o Probably due to peripheral fluid retention and increased Vd

Question 208

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

Answer 208

o Dosage increase of 1.5-2 fold are indicated

Question 209

Will volume of distribution affect drug elimination?

Answer 209

o Yes

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

Question 210

What happens with drug clearance in critical illness?

Answer 210

o CI normally decreases drug clearance

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

Question 211

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

Answer 211

TRUE

Question 212

What is the inoculum effect?

Answer 212

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.

Question 213

What is the impact of a larger inocula?

Answer 213

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.

Question 214

Examples of soluble mediators that can be released by organisms

Answer 214

o Hemolysin, epidermolytic toxin, leukocidin.

o May damage host tissues or alter host response

Question 215

What is a biofilm?

Answer 215

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

Question 216

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

Answer 216

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.

Question 217

If aminoglycosides cause nephrotoxicity, which drug might help?

Answer 217

NAC may decrease damage

Question 218

Do all FQ cause retinal damage in cats?

Answer 218

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

Question 219

Advantages of deescalation

Answer 219

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.

Question 220

What antimicrobials are B lactam?

Answer 220

o Penicillins, cephalosporins and carbapenems

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

Question 221

How do B lactam do their action?

Answer 221

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)

Question 222

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

Answer 222

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.

Question 223

T/F Ampicillin has poor oral bioavailability

Answer 223

TRUE

Question 224

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

Answer 224

TRUE

Question 225

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

Answer 225

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.

Question 226

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

Answer 226

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

Question 227

Which bacteria can typically produce B lactamase?

Answer 227

o Staphylococcus and most G- rods

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

Question 228

Extended-spectrum β-lactamase (ESBL)

Answer 228

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.

Question 229

How is the resistant mechanism of MRSA?

Answer 229

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.

Question 230

Penicillin G

Answer 230

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.

Question 231

Extended-spectrum penicillins (=aminopenicillins)

Answer 231

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.

Question 232

What are the antipseudomonal penicillins?

Answer 232

Piperacillin and ticarcillin

Question 233

First generation cephalosporines

Answer 233

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

Question 234

Second generation cephalosporines

Answer 234

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.

Question 235

Third generation cephalosporines

Answer 235

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

Question 236

Is MRSA resistant to carbapenems?

Answer 236

Yes

Question 237

Carbapenems

Answer 237

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.

Question 238

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

Answer 238

TRUE

Question 239

Aminoglycosides MOA

Answer 239

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.

Question 240

Aminoglycosides spectrum of activity

Answer 240

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.

Question 241

How are aminoglycosides normally administered?

Answer 241

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.

Question 242

Can aminoglycosides be given aerosolized?

Answer 242

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.

Question 243

Aminoglycosides pharmacology

Answer 243

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.

Question 244

What is adaptive resistance?

Answer 244

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.

Question 245

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

Answer 245

o 8 to 10

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

Question 246

What is the trough level

Answer 246

o The lowest concentration in plasma of a drug

Question 247

Aminoglycosides monitoring guidelines

Answer 247

Question 248

Nebulized gentamicin

Answer 248

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.

Question 249

Aminoglycosides toxic effects

Answer 249

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

Question 250

Aminoglycosides and neuromuscular junction

Answer 250

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.

Question 251

Aminoglycosides and ototoxicity

Answer 251

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.

Question 252

Aminoglycosides and nephrotoxicity

Answer 252

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.

Question 253

Aminoglycosides and nephrotoxicity - 2

Answer 253

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.

Question 254

T/F Fluoroquinolone antibiotics are entirely synthetic

Answer 254

TRUE

Question 255

Fluoroquinolone structure

Answer 255

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.

Question 256

FQ’s generations

Answer 256

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.

Question 257

FQ’s MOA

Answer 257

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-.

Question 258

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.

Answer 258

TRUE

Question 259

FQ’s spectrum

Answer 259

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.

Question 260

FQ’s PK/PD

Answer 260

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.

Question 261

FQ’s synergy

Answer 261

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

Question 262

FQ’s resistance

Answer 262

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.

Question 263

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

Answer 263

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

Question 264

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

Answer 264

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.

Question 265

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

Answer 265

seizures and neurologic sequelae.

Question 266

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.

Answer 266

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.

Question 267

FQ’s adverse effects

Answer 267

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.

Question 268

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

Answer 268

TRUE

Question 269

Macrolides with the greatest clinical efficacy generally are derived from _________

Answer 269

Erythromycin

Question 270

Macrolides MOA

Answer 270

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.

Question 271

Macrolides spectrum

Answer 271

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.

Question 272

Macrolides PK/PD

Answer 272

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.

Question 273

Macrolides resistance

Answer 273

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.

Question 274

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

Answer 274

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.

Question 275

In which conditions is typically used erythromycin?

Answer 275

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.

Question 276

Azithromycin

Answer 276

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.

Question 277

Metronidazole spectrum

Answer 277

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.

Question 278

Metronidazole MOA

Answer 278

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.

Question 279

Metronidazole PK/PD

Answer 279

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

Question 280

Metronidazole adverse effects

Answer 280

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.

Question 281

Chloramphenicol MOA

Answer 281

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.

Question 282

Chloramphenicol spectrum

Answer 282

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.

Question 283

Chloramphenicol PK/PD

Answer 283

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.

Question 284

Chloramphenicol adverse effects

Answer 284

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.

Question 285

What drugs include the tetracycline class?

Answer 285

Doxycycline, tetracycline, oxytetracycline and minocycline.

Question 286

Tetracyclines MOA

Answer 286

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.

Question 287

Tetracyclines PK/PD

Answer 287

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.

Question 288

Tetracyclines spectrum

Answer 288

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.

Question 289

Tetracylines adverse effects

Answer 289

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.

Question 290

What antibiotics are in the potentiated sulfonamide class?

Answer 290

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

Question 291

Sulfonamides MOA

Answer 291

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.

Question 292

Sulfonamides spectrum

Answer 292

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.

Question 293

Sulfonamides adverse effects

Answer 293

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.

Question 294

Vancomycin MOA

Answer 294

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.

Question 295

Vancomycin spectrum

Answer 295

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.

Question 296

Vancomycin PK/PD

Answer 296

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.

Question 297

Polymyxins

Answer 297

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.

Question 298

Polymyxin E (colistin) spectrum

Answer 298

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.

Question 299

Clindamycin MOA and PK/PD

Answer 299

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.

Question 300

Clindamycin spectrum

Answer 300

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.

Question 301

What is inducible resistance to clindamycin?

Answer 301

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.

Question 302

Clinical uses of clindamycin

Answer 302

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.

Question 303

Rifampin

Answer 303

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.

Question 304

Newer agents against MDR G+ cocci

Answer 304

Daptomycin

Tigecycline

Quinupristin-Dalfopristin

Linezolid

Question 305

Daptomycin

Answer 305

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.

Question 306

Tigecycline

Answer 306

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.

Question 307

Quinupristin-Dalfopristin

Answer 307

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.

Question 308

Linezolid

Answer 308

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.

Question 309

Suggested empirical antibiotic treatment based on site of infection

Answer 309

Question 310

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

Answer 310

TRUE

Question 311

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 __________

Answer 311

Streptococci

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

Question 312

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

Answer 312

Question 313

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

Answer 313

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.

Question 314

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.

Answer 314

TRUE

Question 315

Antibiotic selection when first treatment has failed and resistance is suspected

Answer 315

Question 316

What is perfusion rate–limited drug diffusion

Answer 316

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

Question 317

What is permeability rate–limited drug diffusion.

Answer 317

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.

Question 318

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

Answer 318

FALSE - lipophilic drugs

Question 319

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

Answer 319

100

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

Question 320

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.

Answer 320

TRUE

Question 321

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

Answer 321

o Fluoroquinolones.

o Lincosamides (clindamycin, lincomycin).

o Tetracyclines (doxycycline, minocycline)

o Macrolides (erythromycin, clarithromycin, azithromycin)

Question 322

Examples of local tissue factors that may decrease antimicrobial effectiveness

Answer 322

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).

Question 323

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

Answer 323

TRUE