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Pharmacology - PMC 621 > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

What are the main gram positive bacteria?

A
  • Staphylococcus (CoNS, aureus, MRSA)
  • Streptococcus (pyogenes, pneumonia, PCN-resistant)
  • Enterococcus (faecalis, faecium, VRE)
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2
Q

What are the main gram negative bacteria?

A
  1. Piddly - easiest to treat
    • Haemophilus
    • Moraxella
    • Morganella
    • Shigella
    • Salmonella
    • Providencia
    • Neisseria
  2. Fence (PEK) - sometimes easy, sometimes hard
    • Proteus
    • Escherichia coli (E. coli)
    • Klebsiella
  3. SPACE - toughest to treat
    • Serratia
    • Pseudomonas
    • Acinetobacter
    • Citrobacter
    • Enterobacter
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3
Q

What are the main atypical bacteria?

A
  • Chlamydia
  • Mycoplasma
  • Legionella
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4
Q

What are the main anaerobic bacteria?

A
  • Peptostreptococcus (mouth)
  • Bacteroides (small intestine)
  • Clostridium (large intestine)
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5
Q

What antibiotics target cell wall synthesis?

A
  1. Beta Lactams
    • Penicillins
    • Cephalosporins
    • Carbapenems
    • Monobactams
    • Aztreonam
  2. Vancomycin
  3. Bacitracin
  4. Cycloserine
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6
Q

What types of antibiotics target the cell membrane?

A
  • Polymyxins
  • Daptomycin
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7
Q

What types of antibiotics target DNA/RNA synthesis?

A
  1. DNA Gyrase
    • Fluoroquinolones (newer version of Quinolones)
  2. RNA Polymerase
    • Rifampin
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8
Q

What antibiotics target folate synthesis?

A
  • Sulfonamides
  • Trimethoprim
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9
Q

What antibiotics target protein synthesis?

A
  1. Targets 50S subunit
    • Macrolides
    • Clindamycin
    • Linezolid
    • Chloramphenicol
    • Streptogramins
  2. Targets 30S subunit
    • Tetracyclines
    • Aminoglycosides
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10
Q

What antibiotics are resisted due to efflux?

A
  • Fluoroquinolones
  • Aminoglycosides
  • Tetracyclines
  • B-lactams
  • Macrolides
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11
Q

What antibiotics are resisted due to immunity and bypass?

A
  • Tetracyclines
  • Trimethoprim
  • Sulfonamides
  • Vancomycin
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12
Q

What antibiotics are resisted due to the bacterial target being modified?

A
  • Fluoroquinolones
  • Rifamycins
  • Vancomycin
  • Penicillins
  • Macrolides
  • Aminoglycosides
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13
Q

What antibiotics are resisted due to enzymes that inactivate them?

A
  • B-lactams
  • Aminoglycosides
  • Macrolides
  • Rifamycins
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14
Q

What are bactericidal agents vs bacteriostatic agents?

A
  • Bactericidal: Lethal to susceptible microorganisms
    • Ideal scenario for killing bacteria
    • Penicillins, Cephalosporins
  • Bacteriostatic: Inhibitory to growth of susceptible microorganisms
    • Works, but has limitations
    • Sulfonamides
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15
Q

What is narrow spectrum vs broad spectrum of activity?

A
  • Narrow spectrum: Effective against a small number of microorganisms
    • Pen G: Gram + organisms (Strep)
    • Nafcillin: Staph and Strep
  • Broad: Effective against a large number of microorganisms
    • Piperacillin/Tazobactam
    • Imipenem: Gram +, Gram -, Anaerobic organisms
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16
Q

What are resistant microorganisms?

A
  • Microorganisms where the concentration of a drug required to inhibit or kill them cannot be achieved safely
  • Intrinsic resistance
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17
Q

What is synergy and what are some examples?

A
  • Synergy: enhancement of action of one drug by another
  • Trimethoprim/Sulfamethoxazole
    • Sequential inhibition of folic acid synthesis
  • Penicillin/Aminoglycoside
    • Increased penetration of aminoglycoside as penicillin breaks down the cell wall
      * Enterococcus
    • Different site for mechanism of action
      * Pseudomonas
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18
Q

What is antagonism and what is an example?

A
  • Antagonism: decreased action of one drug by another
  • Bacteriostatic/Bactericidal
    • Most cidal agents require active cell division or active protein synthesis for expression of their bactericidal activity
    • Many static agents inhibit these “active” processes
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19
Q

What is the postantibiotic effect (PAE) and what are some examples of antibiotics that have this effect?

A
  • PAE: persistent effect of an antimicrobial on bacterial growth following brief exposure of organisms to a drug
  • Aminoglycosides
  • Fluoroquinolones
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20
Q

What is the difference between concentration vs time dependent killing?

A
  • Concentration dependent killing
    • Killing dependent on peak concentration
    • Optimal kill occurs when the concentration exceeds 10x MIC (minimum inhibitory concentration)
    • Quinolones, Aminoglycosides
  • Time dependent killing
    • Killing is dependent on the amount of time the concentration stays above the MIC (40-50%)
    • B-lactam antibiotics
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21
Q

What is the mechanism of action of B-lactams ?

A
  • Inhibits bacterial cell wall synthesis
  • Prevents cross-linking of adjacent peptidoglycan strands, resulting in lysis
  • Targets penicillin-binding proteins (PBPs)
    • Transpeptidases (peptidoglycan transpeptidase)
    • Transglycolases
    • D-alanine carboxykinase
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22
Q

What is the mechanism of action of vancomycin?

A
  • Inhibits cell wall synthesis
  • Inhibits peptidoglycan synthetase and polymerization of linear peptides
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23
Q

What is the mechanism of action of aminoglycosides?

A
  • Inhibits 30S ribosomes
  • Causes misreading of mRNA
  • Inhibits protein synthesis
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24
Q

What is the mechanism of action of chloramphenicol?

A
  • Inhibits peptidyl transferase and peptide band formation
  • Inhibits protein synthesis
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25
Q

What are the mechanisms of action of erythromycin, clindamycin, and lincomycin?

A
  • Inhibits the 50 S ribosome
  • Inhibits protein synthesis
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26
Q

What is the mechanism of action of tetracyclines?

A
  • Inhibits binding of aminoacyl tRNA to ribosomes
  • Targets the 30 S ribosome
  • Inhibits protein synthesis
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27
Q

What is the mechanism of action of streptogramins and linezolid?

A
  • Targets 23 S ribosomes
  • Inhibits protein synthesis
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28
Q

What is the mechanism of action of polymixin B and colistin?

A
  • Interferes with the cell membrane function by using cationic detergent
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29
Q

What is the mechanism of action of rifampin?

A
  • Inhibits DNA-dependent RNA polymerase
  • Overall, interferes with nucleic acid synthesis
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30
Q

What is the mechanism of action of fluoroquinolones?

A
  • Interferes with supercoiling of DNA by action on DNA gyrase (topoisomerase II)
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31
Q

What is the mechanism of action of isoniazid and ethambutol?

A
  • Inhibits lipid synthesis
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32
Q

What is the mechanism of action of sulfonamides and trimethoprim?

A
  • Prevents synthesis of folic acid
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33
Q

What are some things to consider when choosing a route of administration for an antibiotic?

A
  • Oral
    • Mild to moderate infections
  • IV
    • Moderate to severe infections
    • Patient is unable to take oral agents
    • If afebrile for 2-3 days, consider switching to oral
  • IM
    • IV access isn’t obtainable
    • This is only a short term solution
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34
Q

If a patient has a UTI, what should you consider about the route of elimination of different antibiotics?

A
  • Want an antibiotic that is renally excreted
  • Want an antibiotic where a high concentration of the drug is eliminated unchanged
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35
Q

What is the Cockcroft-Gault Equation?

A
  • Used to estimated creatinine clearance rate to determine kidney function
  • [ (140-age) x (weight) ] / [ serum creatinine x 72 ]
    • If female, multiple equation by 0.85
  • Can be used for majority of renally excreted drugs
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36
Q

What are the mechanisms of resistance against B-lactams?

A
  • B-lactamase production
    • Staphylococcus, Haemophilus influenza
  • PBP (penicillin binding protein) changes
    • Pneumococcus (strep pneumo), MRSA, Enterococcus
  • Porin channel changes
    • Gram negative organisms
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37
Q

What is the mechanism of resistance used against macrolides?

A

Methyltransferases that alter drug binding sites on 50S ribosomal subunits

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38
Q

What is the mechanism of resistance used against tetracyclines?

A

Transport systems that pump drugs out of the cell

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39
Q

What are the mechanisms of action used against sulfonamides?

A
  • Increased PABA formation
  • Target enzyme sensitivity
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40
Q

What is the mechanism of resistance used against fluoroquinolones?

A
  • The target enzyme changes
  • Drug efflux
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41
Q

What are superinfections and what is the cause?

A
  • Alterations in normal flora results in the removal of inhibitory influences in the body, which can lead to superinfections
  • Usually due to broad spectrum antibiotics
  • Enterobacteriaceae (PEK, SE)
  • Candida spp.
  • C. diff
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42
Q

What antibiotics are used for SPACE bug coverage?

A
  • Aztreonam - used in cases with anaphlaxis allergic reactions
  • Last resort is Colistin (kitchen sink)
  • Only choose 1 from each row
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43
Q

What are the pharmocokinetic principles of elimination for penicillins?

A
  • Renal elimination - most important route of elimination for most PCNs
  • Optimize dose for varying renal function levels
    • Adjustment for renal insufficiency is a must
    • Allows for high concentrations in the urine
    • Minimizes side effects from accumulation
  • Infants excrete PCNs at slower rate due to immature transport system
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44
Q

What are the pharmacokinetic properties of absorption for penicillins?

A
  • Majority of PCNs yield peak levels 1-2 hours after ingestion
  • Food delays and decreases absorption
    • EXCEPTIONS: Amoxicillin, Pen V, Carbenicillin
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45
Q

What are the acid-stable PCNs?

A
  • Penicillin VK
  • Oxacillin
  • Cloxacillin
  • Dicloxacillin
  • Nafcillin
  • Ampicillin
  • Amoxicillin
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46
Q

Which PCNs are acid-labile?

A
  • Penicillin G
  • Methicillin
  • Carbenacillin
  • Ticarcillin
  • Mezlocillin
  • Piperacillin
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47
Q

What are the pharmacokinetic properties of distribution for PCNs?

A
  • Well distributed to:
    • Lung, liver, muscle, kidney, bone, placenta
  • Levels are sufficient to inhibit bacteria in:
    • Abscesses
    • Middle ear
    • Pleural
    • Peritoneal
    • Synovial fluids
  • Insoluble in lipid
    • Unless inflammation is present, there is poor distribution to the brain, CSF, and prostate
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48
Q

What is the most common adverse effect documented for PCNs?

A

Hypersensitivity reactions
* Hypersensitivity to one PCN means probable hypersensitivity to all PCNs
* All PCNs have equal potential for inducing allergic reaction
* May occur on the first exposure or upon unknown re-exposure
* Types
* Immediate (anaphylaxis) - IgE mediated (E for emergency)
* Delayed (rash) - IgM or IgG. Maculopapular rash is most common

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49
Q

What are some adverse effects of PCNs?

A
  • Hypersensitivity reaction (most common)
  • Eosinophilia
  • Interstitial Nephritis
  • Pseudomembranous Colitis
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50
Q

What is Penicillin G? What are some different variations?

A
  • Penicillin G is a natural penicillin
  • Not very soluble, makes it harder to absorb
  • Four variants:
    • Benzathine Penicillin (IM)
      * Sustained release
      * Prophylaxis in rheumatic fever
    • Procaine Penicillin G (IM)
    • Penicillin G with sodium salt
      * Has sodium salt to help with solubility
    • Pencillin G VK (v potassium)
      * Has potassium salt to help with solubility
  • Pen VK must be used for oral administration - others are acid labile
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51
Q

What bacteria are resistant to Penicillin G/VK?

A

Some gram positive organisms
* Staph produce B-lactamases: 99% resistant
* Streptococcus pneumoniae resistant
* PBP changes
* Gonorrhea resistance occuring

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52
Q

What are some anti-staphylococcal pencillins? Why do they work against staphylococci?

A
  • Penicillinase resistance
  • They are resistant to B-lactamase enzymes produced by bacteria
  • IV
    • Methicillin
    • Oxacillin
    • Nafcillin (hepatic elimination)
  • PO
    • Cloxacillin
    • Dicloxacillin
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53
Q

What are aminopenicillins and what are the different types? What are the adverse effects?

A
  • Penicillins with an amino group that allows for penetration into gram negative cell wall
  • Ampicillin - QID
  • Amoxicillin - TID
  • Adverse effects:
    • Hypersensitivity
    • Diarrhea
      * Take with food to decrease sx
  • When taken with food:
    • Amoxicillin - absorption not impaired
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54
Q

What is the spectrum for aminopenicillins?

A
  • Streptococcus
  • Enterococcus
  • Haemophilus (non B-lactamase producing)
  • Salmonella/Shigella (non B-lactamase producing)
  • Proteus mirabilis, E. coli, +/- Klebsiella
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55
Q

What are carboxypenicillins? What are the adverse effects?

A
  • Carboxypenicillins have increased permeability to cell wall
  • Carbenicillin
    • Indanyl salt - stable oral form (Geocillin)
    • High urine concentrations
    • Body normally cannot tolerate high dosages necessary for concentrations to treat systemic infections
  • Ticarcillin
    • 2-4x more active than Carbenicillin against Pseudomonas
    • Can be significant (so restrict use)
  • Adverse effects:
    • Hypersensitivity
    • Platelet dyfunction (dose dependent side effect caused by carboxy group)
    • Na+ overload
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56
Q

What bacteria can carboxypenicillins inhibit?

A
  • Streptococcus
  • Piddly/PEK
  • SPACE bugs
    • Pseudomonas aeruginosa (high concentration necessary)
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57
Q

What is the spectrum of activity for Ureidopenicillins?

A
  • Bacteroides fragilis (non B-lactamase producing strain)
  • Streptococcus, enterococcus
  • PEK bugs
  • SPACE bugs
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58
Q

What are some ureidopenicillin drugs?

A
  • Mezlocillin
  • Piperacillin
  • Azlocillin
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59
Q

What are the b-lactamase inhibitor/penicillin combo drugs? What is the advantage of using them?

A

Combo drugs
* Augmentin - amoxicillin + clavulanic acid
* Unasyn - ampicillin + sulbactam
* Timentin - ticarcillin + clavulanic acid
* Zosyn - piperacillin + tazobactam

Advantages:
* Adds staphylococcus coverage
* Adds anaerobic coverage

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60
Q

In the structure of cephalosporins, what do the 2 R groups control?

A
  • R1 - Spectrum of activity, PBP affinity, B-lactamase susceptibility
  • R2 - Stability, metabolism, adverse effects, drug interactions, protein binding, t1/2
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61
Q

What are the general absorption properties for cephalosporins?

A
  • Oral agents
    • Rapidly and completely absorbed
  • Available as prodrug esters and nonesterified compounds
  • Prodrug esters
    • Cefuroxime axetil (Ceftin - 2nd gen)
    • Cefpodoxime proxetil (Vantin PO - 3rd gen)
    • Hydrolyzed in intestines to the active drug
    • Food enhances absorption
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62
Q

What are the general mechanisms of action for cephalosporins?

A
  • Binds to PBPs
    • Inhibits crosslinking of peptidoglycan strands
  • Efficacy of each is related to affinity to PBPs
  • Can be susceptible to some B-lactamases
  • Similar in MOA to PCNs
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63
Q

What are the general distribution properties for cephalosporins?

A
  • Well distributed to a variety of body tissues and fluids
  • CSF penetration especially with inflamed meninges
    • 3rd gen cephalosporins (Ceftriaxone) are great choice for various meningitis bacterial infections
    • Requires high dose
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64
Q

What are the general metabolism/excretion properties for cephalosporins?

A
  • Renal excretion
    • All agents except 2 below
    • Dosage adjustments in patients with renal insufficiency
  • Hepatic elimination
    • Ceftriaxone, Cefoperazone
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65
Q

What are the general adverse effect for cephalosporins?

A
  • Hypersensitivity reaction
    • Rash, drug fever
    • 5-15% cross reactivity with PCNS
    • Do not use in patients who had anaphylaxis (or other severe reaction) to PCNs
  • Bleeding
    • NMTT side chain
    • Cefamandole, cefoperazone
    • Disturbance in vitamin K dependent clotting factors
  • ** Alcohol, disulfiram-like intolerance**
    • Agents with NMTT side chain (Cefamandole, Cefaperazone)
  • GI symptoms
    • Diarrhea
    • C. diff (also called Pseudomembranous colitis)
  • Interstitial nephritis
    • Rare
    • Cephalosporins are “close cousins” PCNs
    • Remember - Methicillin PCN taken off market for this SE
  • Serum sickness in children
    • Cefaclor (Ceclor - 2nd gen)
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66
Q

What cephalosporins have the NMTT side chain? What does this mean?

A
  • Cefamandole, Cefaperazone
  • Can cause unique adverse effects such as:
    • Alcohol intolerance
    • Bleeding
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67
Q

What are the general drug interactions for cephalosporins?

A
  • Warfarin
    • Potentiation of anticoagulant effects
  • Alcohol
    • Disulfiram-like reaction
    • Agents with NMTT side chain only
  • Probenecid
    • Prolongs excretion in cephalosporins that have tubular secretion
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68
Q

What are the 1st gen cephalosporins? What is their spectrum of action?

A

Oral:
* Cephalexin (Keflex) «
* Cefadroxil

Parenteral:
* Cefazolin «

Spectrum:
* Staph, Strep
* Piddly, Ecoli

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69
Q

What are the 2nd gen cephalosporins (non cephamycins)? What is their spectrum of action?

A

Oral:
* Cefuroxime «
* Cefprozil
* Cefaclor

Parenteral:
* Cefuroxime «

Spectrum:
* Staph, Strep
* PEK, Piddy

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70
Q

What are the 2nd gen cephalosporins (cephamycins)? What is their spectrum of action?

A

Parenteral:
* Cefoxitin «
* Cefotetan «

Spectrum:
* Staph, Strep
* PEK, Piddly
* Anaerobes (Bacteroides) «

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71
Q

What are the 3rd gen cephalosporins (non antipseudomonal)? What is their spectrum of action?

A

Oral:
* Cefixime
* Cefdinir
* Cefopodoxilme

Parenteral:
* Ceftriaxone «
* Cefotaxime

Spectrum:
* Strep
* SACE (+ PEK, Piddly)

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72
Q

What are the 3rd gen cephalosporins (antipseudomonal)? What is their spectrum of action?

A

Parenteral:
* Ceftazidime «
* Cefoperazone

Spectrum:
* Poor Gram +
* SPACE (+ PEK, Piddly)

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73
Q

What are the 4th and 5th gen cephalosporins? What is their mechanism of action?

A

Parenteral:
* Cefepime «
* Ceftaroline «
* Ceftaz-avibactam «
* Ceftolozane/tazobactam «

4th gen spectrum:
* Staph, Strep
* SPACE (PEK, Piddly)

5th gen spectrum:
* Staph, Strep
* SCE

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74
Q

What do cephalosporins generally not cover?

A
  • Enterococcus
    • Exception: Ceftaroline (4th/5th gen)
  • MRSA
    • Exception: Ceftaroline (4th/5th gen)
  • Chlamydia, Mycoplasma, Legionella (CML - atypicals)
  • Listeria monocytogenes
  • Anaerobes (Bacteroides)
    • Exception: Tan Fox (2nd gen cephamycins - Ce fox itin, Cefote tan )
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75
Q

What is important about Ceftolozane/tazobactam?

A
  • 4th/5th gen cephalosporin with B-lactamase inhibitor
  • Approved for complicated UTIs
  • Very expensive
  • Decrease efficacy observed in patients with moderate renal function
    • CrCL 30<50 mL/min, not bad renal function, not great
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76
Q

What is important about Ceftazidime-avibactam?

A
  • 4th gen cephalosporin with B-lactamase inhibitor
  • Can be used for very resistant bacteria and complicated cases
    • Save for only more resistant bacteria
  • Very expensive
  • Clinical cure rates were low in subgroups with decreased renal function
    • CrCl < 31-50 mL/min (Not terrible, not great)
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77
Q

What are generally the best cephalosporins to use in these cases:
* Community Aquired Pneumonia (CAP)
* Nosocomial Pneumonia
* Meningitis
* Skin or soft tissue infections

A
  • CAP
    • 3rd gen - recommended in CAP guidelines
    • These do not cover atypical pathogens
  • Nosocomial Pneumonia
    • Ceftaz, Cefepime
    • Consider double coverage for SPACE bugs
  • Meningitis
    • Ceftriaxone
    • 3rd gen - use higher doses
  • Skin or soft tissue infections
    • 1st gen for Staph/Strep (simple cellulitis, non-DM)
    • 2nd gen cephamycins or 3rd/4th gens for severe cases OR diabetic patients
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78
Q

What are generally the best cephalosporins to use in these cases:
* Surgical prophylaxis
* Febrile neutropenia
* Endocarditis

A

Surgical prophylaxis
* Cefazolin
* Long t1/2
* Covers Staph
* Convenient dosing for Osteomyelitis/MSSA Sepsis
* 2nd gen cephamycins
* Abdominal/GI surgeries

Febrile neutropenia
* Ceftazidime or Cefepime, +/- Vancomycin

Endocarditis
* Depends on organisms

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79
Q

What are the carbapenem antibiotics?

A

DIME
* Doripenem
* Imipenem
* Meropenem
* Ertapenem

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80
Q

What is imipenem? What is the spectrum of activity?

A
  • Carbacephem (carbapenem) B-lactam agent
  • Extensive renal metabolism by the brush border enzyme dehydropeptidase-1
    • Cilastatin added to prevent renal metabolism (Doesn’t add coverage, just enhances pharmacokinetic principles)

Spectrum:
* Staph, Strep, Enterococcus
* SPACE
* Anaerobes
* ESBL organisms (PEK resistant bugs)

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81
Q

What is meropenem-vaborbactam?

A
  • A combo drug: carbapenem + cyclic boronic acid B-lactamase inhibitor
  • Very expensive
  • Reserved for very resistant bugs (particularly resistant to Box-and-one)
  • Precaution:
    • B-lactam allergery
    • Hx of seizures
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82
Q

What carbapenem has the longest half life? How often is it taken?

A
  • Etrapenem - longest half life
  • Allows once daily administration
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83
Q

What are the general adverse effects of carbapenems?

A
  • Seizures
    • Particularly for imipenem
    • Watch for history of epilepsy, seizures, etc.
  • Cross Allergenicity with PCNs
  • Hematologic
    • Anemia, leukopenia, thrombocytopenia
84
Q

What is the spectrum of activity for imipenem?

A
  • Broad spectrum
  • Staph, Strep, Enterococcus
  • SPACE
  • Anaerobes
  • ESBL organisms - PEK resistant bugs
85
Q

What is the spectrum of activity for meropenem?

A
  • Broad spectrum
  • Staph, Strep, Enterococcus
  • SPACE
  • Anaerobes
  • ESBL organisms - PEK resistant bugs
86
Q

What is the spectrum of activity for doripenem?

A
  • Broad spectrum
  • Staph, Strep, Enterococcus
  • SPACE
  • Anaerobes
  • ESBL organisms - PEK resistant bugs
87
Q

When should you use DIM carbapenem drugs? Which one is best?

A
  • Broad spectrum coverage
  • However, should save to use only in resistant cases
  • Covers ESBL organisms - not many drugs cover this
  • Use imipenem and meropenem over doripenem (IM statistically work better than D)
  • Watch for seizures
88
Q

What is ertapenem?

A
  • Carbapenem antibiotic
  • Spectrum:
    • Staph/Strep ( no Enterococcus coverage)
    • Anaerobes
    • ESBL organisms (PEK)
    • No SPACE bugs
    • Not quite as big of gram neg coverage
  • Reserve for:
    • Serious, life threatening illnesses
    • Multi-organism infections
    • Acute necrotizing pancreatitis
    • ESBL organisms «
89
Q

What is aztreonam? When do we use it?

A
  • “Ace in the Hole”
  • Monobactam antibiotic
  • Used when a patient has an anaphylaxis reaction to PCN, use this instead
  • Not quite as good as PCNs, but safer
  • Covers serious gram negative infections
90
Q

What is the general mechanism of action for aminoglycosides?

A
  • Aminoglycoside binds to outer membrane of cell
    • Results in rearrangement of LPS (Lipopolysaccharide)
    • Uptake is energy dependent
    • Source of energy is an electrochemical gradient
    • Gradient is decreased in an anaerobic environment
  • Once across the membrane, the drug is irreversibly trapped into the bacteria cytoplasm
    • AGs bind to the 30S and 50S ribosomal subunit leading to decreased protein synthesis and misreading of mRNA
  • Very high intracellular concentrations
91
Q

Are aminoglycosides static or cidal? Concentration or time dependent?

A
  • Bacteri cidal
    • Mechanism appears static, but its action is cidal. Not fully understood
  • Concentration depenent killing with PAE
    • After exposure to AGs, continued killing occurs
92
Q

What are the general pharmacokinetic properties of aminoglycosides?

A
  • Absorption
    • Poorly absorbed from GI tract
  • Distribution
    • Distributed freely into vascular space
    • Concentration in lungs are 25-50% of those achieved in serum
    • Distribution to CSF is only 20%, even with inflammation
    • HOWEVER, distribution to CSF is much better in neonates
  • Excretion
    • 99% unchanged via glomerular filtration
93
Q

What are the general adverse effects of aminoglycosides?

A
  • Local reactions
    • Thrombophlebitis
  • Nephrotoxicity
    • Usually associated with high troughs
  • Ototoxicity - Impairment of 8th cranial nerve
    • Usually associated with high peaks
  • Neuromuscular blockade (rare)
94
Q

What is the general spectrum of activity for aminoglycosides?

A

Gram negative
* Piddly, PEK, SPACE
* Kanamycin does not cover PACE
Gram positive
* Staph, sometimes - usually use in a combo to cover this
* Enterococcus
* Use combo drug for synergy
* Common combo: Ampillicin + Gent

95
Q

What are the general indications for aminoglycosides?

A
  • Mainly used for serious gram negative infections
  • Can be used in combo drugs
96
Q

What are the specific uses of Streptomycin/Gentamicin?

A
  • TB (Streptomycin - used as a second line)
  • Brucellosis (Gentamycin + TCN or Chloramphenicol)
97
Q

What is the main oral aminoglycoside and when is it used?

A
  • Neomycin
  • Used for:
    • Suppression of intestinal bacterial flora for elective colorectal surgical prophylaxis
    • Hepatic coma - decreases the number of ammonia forming bacteria
    • Hyperlipidemia - reduces cholesterol absorption
98
Q

What is the main things to check/consider when individualizing doses for aminoglycosides?

A
  • Monitor peak and trough values
    • Keep trough > 2 mcg/mL
    • Peak concentrations depend on location
  • Consider the Hartford Nomogram, but assess level frequently
  • Large daily doses may be equally as effective as smaller multi-daily doses, but with lower toxicity (b/c peaks and troughs)
  • Rely on PAE
  • Narrow therapeutic index
99
Q

What is vancomycin? What is the mechanism of action?

A
  • Glycopeptide antibiotic derived from streptomyces orientalis

Mechanism of action
* Inhibits biosynthesis of peptidoglycan during cell wall formation
* Complexes with D-alanyl-D-alanine precursor
* Bacteri cidal , for multiplying organisms
* Exhibits PAE

100
Q

What are the general pharmacokinetic principles of vancomycin?

A

Absorption
* Poorly absorbed from GI tract
* IV only for systemic infections
* Oral route for C.dif

Distribution
* Distributed freely into most body fluids and tissues (if IV)
* Distribution to CSF only with inflammation

Excretion
* Excreted almost entirely unchanged via glomerular filtration

Half life
* 6-12 hours
* Dosing interval Q8, 12, 24, 48 hours

101
Q

What are the general adverse effects of vancomycin?

A
  • Local reactions
    • Thrombophlebitis
  • Red-Man Syndrome (Vancomycin Infusion Reaction) «
    • Histamine-like reaction
  • Hematologic reactions
    • Neutropenia
    • Eosinophilia
    • Thrombocytopenia
  • Hypersensitivity
    • Maculopapular rash
  • Nephrotoxicity
    • More common with concomitant AGs or other nephrotoxic agents
    • Oral vancomycins do not have nephrotoxicity risk due to breakdown in intestines
  • Ototoxicity
    • Correlates with high peak
102
Q

What is the spectrum of action for vancomycin?

A
  • Gram Positive
    • Staphylococcus aureus (including MRSA )
    • Staphylococcus epidermidis (including MRSE )
    • Streptococcus spp.
    • Enterococcus spp.
    • Clostridium spp.
    • Bacillus anthracis
    • Corynebacteria

Does not work for VRE

103
Q

What are the indications for using vancomycin?

A
  • Serious B-lactam resistant gram positive infections
  • C. diff infection
  • Prophylaxis for major surgical procedures involving implantation of prosthetic materials
  • Surgical prophylaxis
  • Prophylaxis for endocarditis in patients at high risk for endocarditis
104
Q

When should you avoid vancomycin?

A
  • Routine surgical prophylaxis
  • Empiric therapy in febrile neutropenic patients
    • Unless: evidence of possible gram positive infection in hospital setting
  • Eradication of MRSA colonization
  • Continued empiric use in patients whose cultures are negative
  • Gram negative infections
  • Treatment of B-lactam-sensitive gram positive infections in patients with renal failure
105
Q

What are the similarities and differences of vancomycin and aminoglycosides?

A
  • Both have risk of nephrotoxicity/ototoxicity
  • In both, monitor peaks and troughs
  • Vancomycin - gram positive
  • Aminoglycosides - gram negative
106
Q

What is the mechanism of action of Quinupristin/Dalfopristin (Synercid)? Used for what?

A

Mechanism of action
* Irreversibly binds to the 50S bacterial ribosomal subunit
* Quinupristin - inhibits chain formation, resulting in early termination
* Dalfopristin - inhibits peptide elongation by interfering with peptidyl transferase
* Individually - static, combo - cidal

Used for:
* MRSA
* PCN resistant strep pneumo
* VRE
* Covers E. faecium, but not great
* Anaerobes
* Some gram negative

IV only

107
Q

What is Linezolid? What is the mechanism, coverage, drug interactions, adverse effects?

A

Mechanism:
* Oxazolidinone class
* Binds to 23S rRNA of 50S subunit

Used for:
* MRSA, VISA, VRE, PCN-resistance strep pneumo
* Can be IV or PO (both 100% bioavailability)

Adverse effects:
* Myelosuppression - thrombocytopenia
* Superinfection (Yeast)
* Mitochondrial toxicity - long course

Interactions:
* MAOI
* Watch with co-administration of SSRIs for serotonin syndrome

108
Q

What is Tedozolid? Mechanism, coverage, adverse effects, drug interactions?

A

Mechanism:
* Oxazolidinone class
* Binds to 23S rRNA of 50S subunit
* Reversible MAOI

Used for:
* Most resistant gram positives - MRSA, VISA, VRE, PCN-resistant strep pneumo
* IV = PO (100% bioavailability)

Adverse effects:
* Thrombocytopenia, neutropenia, paresthesias, blurred vision

Interactions:
* MAOI, watch for co-administration with SSRIs

Pearl:
* Breast cancer resistance protein (BCRP) inhibitor in intestine

109
Q

What is Telavancin? Spectrum, adverse effects, pros and cons

A
  • Glycolipopeptide

Spectrum:
* Gram positive - Staph (MRSA), Strep, Enterococcus

Adverse effects:
* Contraindication with concomitant IV unfractionated heparin infections «
* May falsely elevate INR
* Nephrotoxicity
* Red man syndrome with infusion
* Increased mortality for patients with renal dysfunction
* Risk of fetal development toxicity

Cons:
* Semi-synthetic derivative of Vancomycin
* May have cross sensitivity with vanco
* Same side effects
* REMS program watch list

Pros:
* No need to monitor peaks/troughs

110
Q

What is oritavancin? Coverage, adverse effects, interactions, pros/cons

A
  • Glycolipopeptide
  • Single dose per week - but costs $1500-2000 per dose

Interactions:
* Weak inhibitor of 2C9 and 2C19, and weak inducer of 3A4 and 2D6
* May increase bleed risk with warfarin

Adverse effects:
* Infusion related reaction (red-man syndrome)
* Monitor LFTs and SCr

Coverage:
* Gram positive - Staph (MRSA), Strep, Enterococcus
* Approved for skin and soft tissue infections

111
Q

What is dalbavance? Coverage, interactions, pros/cons

A
  • Glycolipoptide
  • Single or double dose per week
  • May use with CrCl < 30mL/min, but not dialysis

Coverage:
* Gram positive (including MRSA)
* Approved for skin and soft tissue infections

Interaction:
* CAN use with warfarin

112
Q

What is Colistin? Coverage, administration, adverse effects

A
  • Polymyxin E antibiotic - bacteriocidal
    • Polymyxin B - OTC triple antibiotic ointment

Coverage:
* SPACE bug coverage (+ Piddly, PEK)

Administration:
* Prodrug
* Mainly IV, some inhaled or intrathecal (but rare)
* Dose based on colistin base activity (CBA)

Adverse effects:
* Nephrotoxicity
* Neurotoxicity

“Kitchen Sink:
* Reserved for last ditch effort, when Box-and-One doesn’t work
* Used especially for PA in SPACE bugs, resistant PEK, Pan-resistant gram negative organisms

113
Q

What is Fosfomycin? Coverage, dose, adverse effects

A
  • Phosphoric acid derivative, bacteriocidal
  • Covers only UTIs (low serum concentration) - also called cystitis
    • Gram positive and gram negative organisms
    • MRSA/VRE
    • ESBL
  • Dose - 1 packet dose, PO
  • Adverse effects: mostly GI
114
Q

What is tigecycline? What does it cover?

A
  • Glycylcycline agent - bacteriorstaic
  • Very expensive

Coverage:
* MRSA/VRE
* Gram negative
* Acinetobacter (not pseudomonas)
* Anaerobes (GI infections)
* Approved for complicated skin infection, intra-abdominal infections, community acquired pneumonia
* Does not cover bacteremia, does not attain high serum concentrations

115
Q

What is daptomycin? Coverage, adverse effects

A
  • Lipopeptide (bacteriocidal)

Covers:
* Gram positive - very well
* MRSA, VRE
* Complicated skin and soft tissue infections
* Bacteremia, right sided endocarditis
* Does not cover pneumonia
* Inactivated by pulmonary surfactant

Adverse effects:
* Rhabomyolysis
* Monitor CPK baseline and weekly
* Eosinophilic pneumonia (rare)

116
Q

What is mupirocin?

A
  • Topical treatment (cream/ointment 2%)
  • MRSA colonization eradication from Nares
  • Controversial regarding long term efficacy of eradication
  • Other uses: Impetigo, infected wounds
117
Q

What is the general mechanism of action for sulfonamides?

A
  • Bacteria require tetrahydrofolic acid (derivative folic acid), which is a cofactor in the synthesis of thymidine, purine, DNA
  • Bacterial cell walls are impermeable to folic acid, so they must synthesize it from PABA
  • Sulfonamides compete with PABA for the enzyme dihydropteroate synthetase
    • Sulfonamides may have an increased affinity for the enzyme, compared to PABA
  • Host cells are not affected b/c they require pre-formed folic acid (cannot synthesize it).
  • Sulfonamides = bacteriostatic
118
Q

What are the general adverse reactions of sulfonamides?

A
  • Anaphylaxis
  • Cutaneous reactions
    • Morbilliform rash
    • SJS
    • Erythema Multiforme
    • Photosensitivity reaction
  • Hematological rash
  • Hypersensitivity reaction
    • Drug fever, rash
  • Nephrotoxicity
    • Crystalluria w/less soluble compounds (Sulfadiazine, Sulfathiazole)
    • Administer with fluids, check hydration status of patients prior to use
  • Kernicterus
    • Pregnancy - competes for bilirubin binding sites on plasma albumin
    • Results in increased fetal blood levels of unconjugated bilirubin
119
Q

How are sulfonamides excreted?

A
  • Excreted via glomerular filtration
  • Extent of glomerular filtration varies with each agent
120
Q

What is the general spectrum of activity for sulfonamides?

A
  • Gram Positive
    • Staph (MRS), Strep
    • Bacillus anthracis
  • Gram Negative
    • Piddly, PEK, CE of SPACE
  • Other
    • Chlamydia trachomatis
    • Toxoplasma gondii (protozoa)
    • Plasmodium falciparum (protozoa-malaria)
    • Nocardia
121
Q

What are the mechanisms of resistance against sulfonamides?

A
  • Overproduction of PABA
    • Neusseria, Staph
  • Structural change in dihydropteroate synthetase
    • E. coli
  • Decreased permeability of bacteria to drug
122
Q

What are the indications of use for sulfonamides?

A
  • Uncomplicated UTIs
  • Pneumocystis carinii (tx and prophylaxis)
  • Nocardosis
  • Toxoplasmosis
  • Malaria (Chloroquine-resistant)
  • Rheumatic fever prophylaxis (PCN allergy)
123
Q

What is trimethoprim?

A
124
Q

What is Bactrim?

A
  • Combo drug: Sulfonamide (sulfamethoxazole) + Trimethoprim
  • Sulfonamide - targets dihydropteroate enzyme (PABA –> Folic acid)
  • Trimethoprim - targets dihydrofolate reductase (Folic acid -> Tetrahydrofolic acid)
125
Q

What is the mechanism of action of trimethoprim?

A
  • Inhibits dihydrofolate reductase, which prevents the formation of tetrahydrofolic acid
  • 50,000x more active against bacterial DHFR than the human enzyme
  • Can be bacteriostatic or bacteriocidal
126
Q

What is the excretion and adverse effects of trimethoprim?

A

Excretion:
* Excreted 80% unchanged via glomerular filtration and tubular secretion

Adverse effects:
* Cutaneous Reactions
* Pruitis
* Rash
* GI Reactions
* Nausea, vomiting, diarrhea
* Elevated serum transaminases, bilirubin
* Hematologic Reactions

  • Caution in patients with possible folate deficiency
    • Alcoholics, pregnant women, debilitated patients, malabsorptive syndromes
127
Q

What is the spectrum of action of trimethoprim? Indications?

A

Spectrum:
* Gram positive
* Staph spp., Strep spp., Bacillus anthracis
* Gram negative
* Piddly, PEK, CE of SPACE
* Other
* Pneumocystis carinii - used in conjunction with dapsone

Indications
* Acute uncomplicated UTI
* Recurrent UTI prophylaxis
* Traveler’s diarrhea

128
Q

What is the spectrum of action of Bactrim?

A

Gram positive:
* Staph, strep
* Bacillus anthracis

Gram negative:
* Piddly, PEK, CE from SPACE

Other:
* Nocardia asteroides
* Chlamydia trachomatis
* Toxoplasma gondii (protozoa)
* Plasmodium falciparum (protozoa - malaria)
* Pneumocystic carinii (fungus)

129
Q

What are the indications for Bactrim?

A
  • UTI
    • Uncomplicated UTI
    • Prophylaxis of UTI
    • Acute and chronic prostatitis
  • RTI
    • COPD exacerbations
    • Pneumonia
    • Acute otitis media
    • Acute sinusitis
    • PCP (Px and Tx)
  • GI Infections
    • Salmonella/Shigella
    • Traveler’s Diarrhea
    • Cholera
  • STDs
    • Uncomplicated gonococcal infections
    • Chancroid
    • Bacterial vaginosis
  • Other Infections
    • Stenotrophomonas maltophilia (DOC)
130
Q

What are the drug interactions for Bactrim?

A
  • Warfarin
    • Highly likely to potentiate anticoagulant effects
  • Methotrexate
    • Can displace methotrexate from protein binding sites
    • Increases free methotrexate
131
Q

What is the mechanism of action of nitrofurantion?

A
  • Unclear mechanism
  • Possibly interferes with early stages of bacterial carbohydrate metabolism by inhibiting acetyl CoA
  • Possibly due to production of reactive 5-nitro anion, free radicals
132
Q

What is the distribution and excretion properties of nitrofurantoin?

A
  • Distribution
    • Serum/tissue concentrations are insignificant
    • Urine concentrations are very high
  • Excretion
    • Rate of excretion is linear, related to CrCl
    • Patients with impaired GFR - decrease in efficacy, increase in systemic toxicity
    • Do not use if CrCl < 40-60
133
Q

What are the adverse effects of nitrofurantoin?

A
  • Hypersensitivity reactions
    • Rash
  • Hematologic reactions
    • Hemolytic anemia
  • Hepatotoxicity
  • Peripheral neuropathy
    • Esp. in renal insufficiency
  • GI reactions
    • Nausea, vomiting, diarrhea
    • Less with macrocrystalline preparation, compared to microcrystaline suspension form
  • Pulmonary reactions
    • Acute - hypersensitivity (fever, cough, dyspnea, eosinophilia, infiltrate)
    • Subacute - after 1 month therapy (cough, dyspnea, interstitial infiltrate)
    • Chronic - after 6 months therapy (cough, dyspnea, interstitual infiltrate)

Subacute, chronic reactions are often reversible after drug is stopped

134
Q

What is the spectrum of action for nitrofurantoin? Indications?

A

Gram positive:
* Staph aureus
* Staph saprophyticus
* Enterococcus faecalis
* Enterococcus faecium

Gram negative:
* E. coli
* Klebsiealla pneumonia
* Citrobacter spp.
* Enterobacter aerogenes

Indications:
* Acute uncomplicated UTI treatment
* UTI prophylaxis

135
Q

What is the mechanism of action of methenamine?

A
  • No antibacterial effect alone
  • At adequate urine pH (< 5.5), hydrolyzed to formaldehyde, which kills bacteria by denaturing proteins
  • Urine must sit long enough for this to work. Does not work for catherized patients
136
Q

What are the adverse effects of methenamine?

A
  • Hypersensitivity reactions
    • Rash/Pruritis
    • Hippurate form contains the dye tartrazine - may lead to allergic reactions in asthma patients
  • Hemorrhagic Cystitis
  • GI reactions (nausea, vomiting, diarrhea)
  • Avoid in hepatic insufficiency - ammonia byproduct
  • Renal failure - acid forms could potential lead to systemic acidosis
137
Q

What are the absorption and excretion principles of methenamine?

A

Absorption
* Rapidly absorbed from GI tract
* Excellent bioavailability
* 10-30% of dose can be hydrolyzed to formaldehyde by gastric acid - enteric coated formulation avoids this

Excretion
* t1/2 = 3-4 hours
* Renal clearance is 95% total clearance

138
Q

What is the spectrum of activity and indications for methenamine?

A

Spectrum:
* Virtually all bacteria and fungi are susceptible to formaldehyde
* Certain urease positive bacteria (Proteus) can alkalinize the urine, which stops conversion to formaldehyde

Indications:
* UTI prophylaxis only
* NOT recommended for treatment of acute UTIs

139
Q

What factors affect formaldehyde concentrations when taking methenamine?

A
  • Rate of hydrolysis of methenamine to formaldehyde
  • Rate of urine loss from bladder by voiding or drainage
140
Q

What is the mechanism of action and mechanism of resistance to macrolides?

A

Mech of Action:
* Reversibly binds to 50S-ribosomal subunit of bacteria (decreases protein synthesis)
* Bacteriostatic

Mech of Resistance:
* Decreased permeability of the cell envelope
* Alteration in 50S ribosomal receptor site
* Enzymatic inactivation of erythromycin by esterases

141
Q

What are the absorption properties of erythromycin?

A
  • Erythromycin base
    • Rapidly inactivated by gastric acid
    • Enteric coated and film coated forms decrease this inactivation
  • Base, stearate, and ethylsuccinate
    • Absorbed better in fasting state
  • Emycin Estolate
    • Not affected by food
142
Q

What are the distribution properties of macrolides?

A
  • Distributes in tissues longer than in blood
  • Very high concentration in alveolar macrophages and leukocytes compared to extracellular fluids
  • Azithromycin tissue concentration
    • 10-100x serum concentrations
    • Usually 3-5 day course of therapy, stays in body much longer
143
Q

What are the excretion/metabolism properties of erythromycin, clarithromycin and azithromycin?

A

Erythromycin
* Primarily biliary excretion
* Small percentage in urine
* Large proportion of absorbed drug may be inactivated in liver by demethylation

Clarithromycin
* Metabolized in the liver by oxidation and hydrolysis
* 20-30% of drug excreted into the urine unchanged

Azithromycin
* Small proportion is metabolized
* Mainly biliary excretion
* t1/2 = 68 houts (after multiple doses)

144
Q

What are the adverse effects of erythromycins?

A
  • GI - abdominal cramps, NVD
  • Thrombophelbitis - IV admin
  • Allergic reactions
  • Cholestatis hepatitis (rare)
    • Avoid estolate form in pregnancy
  • Large IV doses - ototoxicity, QT prolongation (rare)
145
Q

What are the adverse effects of clarithromycin and aizthromycin?

A
  • GI symptoms - not as severe as erythromycin
  • HA
  • Dizziness
  • Allergic reactions
146
Q

What are the drug interactions for macrolides?

A
  • Metabolites form inactive complexes with p450 enzymes
  • Decreased metabolism of: Theophylline, Warfarin, Carbamazepine, Cyclosporine

Azithromycin - does not inactivate p450 enzymes

147
Q

What is the spectrum of activity for macrolides?

A

All
* Gram positive (Staph, Strep)
* Atypicals

Clarithromycin & Azithromycin
* Piddly gram negatives
* MAC (Mycobacterium avian complex)

Clarithromycin only
* Helicobacter pylori

148
Q

What are the indications for the macrolides?

A
  • Penicillin allergic patients
  • Community acquired pathogens (Clarithro and azithromycin)
  • Mycoplasma pneumoniae
  • Legionnaire’s disease
  • Chlamydia trachomatis nongonococcal urethritis and cervicitis
  • Chlamydia trachomatis - during pregancy (don’t use estolate form)
149
Q

What is the mechanism of action and pharmacokinetic principles of clindamycin?

A

Mechanism of action:
* Binds to 50S ribosome, leading to inhibition of protein synthesis
* Derived from lincomycin

Pharmacokinetics
* Bioavailability = 90%
* Food delays absorption
* Good tissue penetration
* Good for skin and soft tissue infections
* Metabolized by liver

150
Q

What is the spectrum of activity for clindamycin?

A
  • Strep
  • Staph
    • Limited bactericidal rate compared to B-lactams
  • Anaerobes
    • Bacteroids
    • Clostridium
    • Peptostreptococcus, peptococcus
  • Toxoplasmosis
    • Sulfonamide allergy
151
Q

What are the adverse effects of clindamycin?

A
  • Allergic reactions
  • Diarrhea «
    • 20% of patients
    • More common with oral form
  • C. diff infection
  • Hepatotoxicity (mild and severe)
152
Q

What is chloramphenicol? Mechanism of action, spectrum of activity?

A

Mech of action:
* Reversibly binds to large 50S subunit of the 70S ribosome

Spectrum:
* Gram positive
* Gram negative
* Aerobic and anaerobic organisms
* Rickettsia
* Chlamydia
* Large coverage range

153
Q

What are the general pharmacokinetic principles of chloramphenicol?

A
  • Suspension
    • Must be hydrolyzed in the intestines for active chloramphenicol
  • IV form has incomplete hydrolysis
    • Serum concentrations after IV therapy are only about 70% of those after oral administration
  • Excellent CSF concentrations
    • 30-50% without inflammed meninges
  • Metabolism via glucuronidation in liver
  • Wide variations in metabolism and excretion in children - must monitor serum levels
154
Q

What are the indications for chloramphenicol?

A
  • Bacterial meningitis
    • H. influenza, Strep pneumo, Neisseria meningitidis
    • Penicillin/Cephalosporin allergy
    • Oral alternative if IV cannot be used
  • Rickettsial infections
155
Q

What are the adverse effects of chloramphenicol?

A

Hematologic
* Reversible bone marrow depression due to direct pharmacologic effect on inhibition of mitochondrial protein synthesis
* Anemia, leukopenia, thrombocytopenia

Idiosyncratic Aplastic Anemia
* Majority of cases occur weeks-months after completion of therapy, and is not necessarily dose related

Gray Baby Syndrome
* Abdominal distension, vomiting, cyanosis, circulatory collapse
* Drug accumulates -> toxicity -> vomiting, flaccidity, hypothermia, respiratory collapse, gray color
* Newborns lack effective glucuronic acid conjugation mechanism to degrade/detoxify system

156
Q

What is Gray Baby Syndrome?

A
  • Adverse effect of chloramphenicol
  • Sx: abdominal distension, vomiting, cyanosis, circulatory collapse
  • Fundamental mechanism of toxicity: inhibition of mitochondrial protein synthesis
  • Newborns lack effective glucuronic acid conjugation mechanism that degrades/detoxifies the system
157
Q

What antibiotics are most likely to affect birth control?

A

Rifampin, Tetracyclines, Ampicillin

158
Q

What is the mechanism of action for Quinolones?

A
  • Inhibits bacterial DNA gyrase (topoisomerase II) and topoisomerase IV
    • DNA gyrase is essential for supercoiling of cellular DNA by a nicking, passing through, and resealing process
  • Bactericidal
  • PAE
    • PAE averages 1-2 hours
    • Tends to increase with increasing concentrations and length of exposure
159
Q

What are some safety concerns to watch out for with fluoroquinolones?

A
  • Tendonitis, tendon rupture
  • Peripheral neuropathies
  • Psychiatric disturbances
  • Severe hypoglycemia, coma
  • Risk for aortic dissection and/or rupture
160
Q

What are the guidelines for restricted use of fluorquinolones?

A
  • No longer recommended as first line treatment options for:
    • Uncomplicated UTIs
    • Acute exacerbation of COPD
    • Sinusitis
  • May justify use based on:
    • Allergies
    • Recent antibiotics
    • Cultures (new or recent)
  • Do not use in patients under 18 y/o
161
Q

What are the adverse effects of quinolones?

A
  • Hypersensitivity reactions
    • Photosensitivity
  • Hematologic reactions
    • Neutropenia
    • Eosinophilia
  • Cardiac
    • QT prolongation
  • GI
    • Diarrhea, nausea, vomiting
  • Nephrotoxicity (rare)
  • CNS
    • Headache, dizziness, mental status change
  • MSK
    • Arthropathy
    • Tendon rupture
162
Q

What are some quinolone drug interactions?

A
  • Theophylline
    • Cipro can double Theophylline levels
    • Levofloxacin - little to no effect
  • Antacids, iron, sucralfate, multivitamins
    • Do not give within 2-4 hours of quinolone dose
  • Warfarin
    • Increased anticoagulant effect possibly due to metabolism or protein binding changes
    • Levofloxacin - possibly no effect, but still monitor
163
Q

What is the general spectrum of activity for quinolones?

A

Gram positive:
* Older agents (Cipro, oflox) - not good coverafe
* Newer agents (Levo, moxi, gemi) - better staph/strep coverage

Gram negative:
* Cipro, levo - SPACE
* Moxi - SACE

Anaerobics:
* Moxifloxacin only
* Has indication for complicated abdominal infections

Atypicals:
* Levo, moxi, cipro - cover CML
* Watch for Cipro resistance with Chlamydia

164
Q

What is ciprofloxacin?

A
  • Type of quinolone
  • Generally very good coverage, with wide range of FDA approved indications
    • Not great gram positive coverage, use with another agent
    • Very potent against gram negative organisms, including pseudomonas
  • Excellent bioavailability
    • Use oral form if possible
165
Q

What is the spectrum of action for levofloxacin, gemifloxacin, and moxifloxacin?

A

Gram positive
* All three are good for Staph and Strep
* Excellent for PCN resistant Strep Pneumo

Gram negative
* Levofloxacin (SPACE) potency is less than cipro
* SACE (no P) for gemifloxacin or moxifloxacin

Atypicals
* All three cover CML and mycoplasma (walking pneumonia)

Anaerobics
* Moxifloxacin only

166
Q

What is delafloxacin? Coverage, pearls

A
  • Newest fluoroquinolone (approved 2017)

Coverage:
* Staph, Strep, MRSA
* E. coli, Enterobacter, Klebsiella, Pseudomonas
* Approved for acute bacterial skin and skin structure infections

Pearls:
* No QT prolongation
* No phototoxicity
* No markers of ADRs to liver, kidneys or glucose control
* Retained FDA warning for tendon ruptures, neuropathy, CNS symptoms

167
Q

What are the mechanisms of resistance against quinolones?

A
  • Altered target enzyme (altered DNA gyrase)
  • Reduction of Quinolone concentrations intracellularly
    • Altered drug permeability across cell membrane due to changes in porin channels
    • Efflux of drug from bacterial cells
168
Q

What are the members of the tetracycline family?

A
  • Doxycycline
  • Minocycline
  • Demeclocycline
  • Oxytetracycline
  • Chlortetracycline
  • Tetracycline
169
Q

What is the mechanism of action of tetracyclines?

A
  • Reversibly binds to 30S ribosomal subunit
  • Decreases protein synthesis
  • Bacteriostatic
170
Q

What are some general pharmacokinetic principles of tetracyclines?

A
  • Bioavailability depends on products
    • Doxy, Mino: 90-100%
    • Tetra, Demeclo, Oxy: 58-75%
  • Absorption decreases with food
  • Renal elimination:
    • Tetra, Oxy, Demeclo
  • Hepatobiliary elimination:
    • Doxy, Mino
171
Q

What are the general adverse reactions to tetracyclines?

A
  • Photosensitivity
  • Discoloration of developing teeth
    • Bones and teeth developing during pregnancy and in children through ~8 y/o
  • Reversible diabetes insipidus - Demeclocycline
  • Vestibular effects - Minocycline
    • Dizziness, ataxia, vertigo
  • Fanconi-like Syndrome
    • Associated with outdated citric acid formulation of tetracycline
    • Nausea, vomiting, lethargy, polydipsia, polyuria, proteinuria, acidosis, hypokalemia
172
Q

What are the drug interactions for tetracyclines?

A
  • Decreased absorption of tetracycline agents when co-administered with:
    • Di- and trivalent cations (Ca, Mag, Zinc, Alum, Iron)
    • Antacids
    • Dairy products
  • Potential antagonism effect with bacteriocidal agents
    • Tetracyclines are bacteriostatic. Bacteriocidal agents require active growth
  • Enhances anticoagulation of Warfarin
173
Q

What are some clinical uses for tetracyclines?

A
  • Rickettsia infections (parasites)
    • Rocky Mountain spotted fever
  • Mycoplasma pneumonia
  • Chlamydia infections
    • Urogenital 7 days of doxycycline
  • Acne
  • H. pylori in combo with other agents
174
Q

What is brucellosis? How do you treat?

A
  • In humans, can cause flu-like symptoms (fever, sweats, headaches, back pain, physical weakness)
  • Contracted by coming in contact with infected animals or animal products (cheese, milk)
  • Severe infections of CNS or lining of the heart may occur
  • May cause long-lasting or chronic symptoms such as fever, joint pain, fatigue

Treatment:
* Tetracycline + Gentamicin

175
Q

What is vibrio cholera/vulnificus?

A
  • Acute diarrheal disease, mainly in India and Southeast Asia
  • Causative agent is Vibrio cholerae
  • Condition can lead to severe dehydration in a matter of hours
  • Can cause disease in those who eat contaminated seafood, or have an open wound that is exposed to seawater

Treatment: tetracyclines

176
Q

What is Borrelia burgdorferi?

A
  • Better known as Lyme disease
  • Bull’s eye rash, fever, headache, muscle/joint pain, flu-like symptoms

Treatment: tetracyclines

177
Q

What is the treatment for SIADH? What does SIADH stand for?

A
  • Syndrome of Inappropriate Antidiuretic Hormone
  • Treatment: Demeclocycline
    • Only thing Demeclo is used for
178
Q

What is in the herpes virus family?

A
  • Viral encephalopathy
  • Herpes Simplex Virus 1 (oropharyngeal) & 2 (genital)
    • Herpes simplex labialis (cold sores)
  • Varicella Zoster Virus
    • Chickenpox
    • Zoster (shingles)
179
Q

What is the general viral life cycle?

A
  1. Attachment - mediated by proteins
  2. Entry - cross host membrane
  3. Uncoating - virus loses capsid proteins
  4. Transcription - exposed nucleic acid transcribed to mRNA
  5. Translation
  6. Genome replication
    • RNA virus requires ribonucleic triphosphates
    • DNA virus requires deoxyribonucleoside triphosphates
  7. Assembly
  8. Exiting - via cell lysis or budding
  • Retroviruses have extra steps and occur in a different order
180
Q

What antivirals act by inhibition of viral genome replication?

A
  • Acyclovir
  • Glanciclovir
  • Zidovudine
  • Efavirenz
  • Nucleoside and nucleotide analogues
  • Inhibits polymerase
181
Q

What antivirals work by inhibiting viral uncoating?

A
  • Amantadine
  • Rimantidine
  • Blocks M2 (pH gated proton channel) that opens in response to acidification
182
Q

What antivirals work by inhibition of viral release?

A
  • Oseltamivir
  • Zanamivir
183
Q

What are some common viral infections?

A
  • Herpes Family
    • Varicella (chickenpox), Zoster (shingles), Encephalitis
  • Cytomegalovirus (CMV)
    • Common in transplant patients (retinitis and pneumonia)
  • Influenza
    • Types A and B
  • Hepatitis
    • Types A, B, and C
  • Respiratory Syncytial Virus (RSV)
    • Pneumonia in children
  • HIV
    • Systemic destruction of helper T-cells
184
Q

What is the mechanism of action of acyclovir?

A
  • Active drug (Prodrug is Valacyclovir)
  • Acyclovir phosphorylated to monphosphate form via HZV or VZV thymidine kinase
  • Monophosphate to triphosphate via cellular enzymes –> Chain termination
185
Q

What are the pharmacokinetic properties and adverse effects of acyclovir?

A
  • Bioavailability: 10-30% (IV, PO, topical)
  • Good CSF penetration for treatment of viral meningitis
  • Renally eliminated, requires dose reduction

Adverse effects:
* Reversible nephrotoxicity d/t crystalline nephropathy, more likely with high dose bolus and IV formulations
* CNS (HA, hallucinations, seizures)
* Nausea, vomiting, diarrhea - dose and age dependent
* Hepatic (hyperbilirubinemia)

186
Q

What is Valacyclovir?

A
  • Prodrug (Active form is acyclovir)
  • Bioavailability: 70%
  • PO form only
  • Rapidly converted to acyclovir via intestinal and hepatic metabolism
187
Q

How do you use acyclovir and valacyclovir?

A
  • Best outcome if used within 48-72 hours of appearance of lesion/rash
  • IV Acyclovir is drug of choise (DOC) for Encephalitis
  • Valacyclovir - Zoster and Herpes Simplex (less frequent dosing)
  • Genital Herpes Simplex
    • 1st episode: 10 day treatment
    • Recurrent: 5 day treatment
188
Q

What is HSV Encephalitis?

A
  • One of the most commonly identified causes of viral encephalitis
  • Occurs in all age groups
  • Symptoms:
    • Fever
    • Focal neurologic symptoms, altered mental status
  • Other invasive herpes infections (immunocompromised patients)
    • HSV Esophagitis
    • HSV Pneumonitis
  • Treatment of choice:
    • IV Acyclovir 10 mg/kg for 14-21 days
189
Q

What is Herpes Zoster?

A
  • Reactivation of Varicella Zoster (chicken pox)
  • Risk increases with age, immune statue
  • Unilateral dermatome
  • Painful lesions
  • Complication:
    • Post-herpetic neuralgia
    • Blindness
190
Q

How do you treat Herpes Zoster?

A
  • Steroids
  • Neuropathic pain medicine (Gabapentin, pregabalin, TCAs, NSAIDs)
  • Treatment for painful herpetic lesions
  • Antiviral treatments

Prevention: Shingles vaccine (Zostavax)
* Approved for patients > 50 y/o
* Recommended for patients > 60 y/o

191
Q

What are some topical antiviral agents?

A
  • Docosanol - oral herpes simplex
  • Imiquimod - gential/perianal warts
  • Podofilox - gential/perianal warts
  • Podophyllin - 25% liquid administered in clinic directly to wart
192
Q

What is Cytomegalovirus (CMV)?

A
  • DNA double stranded virus within the Herpes Virus Family
  • Commonly infects advanced immunosuppressed patients and transplant patients
  • Impacts specific organ symptoms:
    • Retinitis
    • Colitis
    • Esophagitis
193
Q

What is Ganciclovir?

A
  • Active drug (pro drug - Valganciclovir)
  • MOA - similar to Acyclovir
    • 10x more potent than Acyclovir for treating CMV
  • Bioavailability = 6-9% (IV, intravitreal, PO)
  • Use for:
    • CMV retinitis prophylaxis + treatment
  • Adverse effects:
    • CNS with behavior changes and headache
    • Nausea, vomiting
    • Neutropenia (15-40%)
    • Thrombocytopenia (5-20%)
194
Q

What is Valaganciclovir?

A
  • Prodrug (active form is Ganciclovir)
  • MOA - Similar to Acyclovir
  • Bioavailability = 60% (PO only)
  • Used for:
    • CMV Retinitis prophylaxis and treatment
    • Can do intravitreal treatment - surgically implanted to treat CMV retinits in AIDS patients
195
Q

What is Penciclovir?

A
  • Active drug (prodrug form is Famciclovir)
  • MOA - similar to Acyclovir
  • Available in US as topical cream
  • Used to treat herpes simplex cold sore treatment
  • Adverse effect: application site irritation
196
Q

What is Femciclovir?

A
  • Prodrug (active form is Penciclovir)
  • MOA - similar to acyclovir
  • Bioavailability: 65-77%
  • Renally excreted
  • Adverse effects: Headache, GI symptoms
  • Used to treat herpes simplex, herpes zoster
  • Best result if started within 72 hours
197
Q

What is Cidofovir?

A
  • Used to treat CMV
    • Must be administered with Probenecid
    • Second line treatment - reserved for CMV retinitis if other treatments fail
    • Administer with normal saline to decrease chances of nephrotoxicity (hydration is key!)
  • MOA - Interacts with DNA polymerase either as an alternative substrate or a competitive inhibitor
  • Adverse effects:
    • Highly nephrotoxic
    • Neutropenia (15%)
198
Q

What is Foscarnet?

A
  • Inorganic phosphate that doesn’t require phosphorylation by thymidine kinase
  • MOA - competes for pyrophosphate in viral DNA polymerases
  • Adverse effects:
    • Nausea, vomiting, diarrhea (25-50%)
    • Nephrotoxic, severe electrolyte imbalances
    • Seizures, anemia (33-50%), neutropenia
    • EKG changes (1st degree AV block, hyper/hypotension)
  • Used for:
    • CMV in AIDS patients, in combo with Ganciclovir for recurrence
199
Q

What is Imiquimod?

A
  • Topical treatment of Condylomata acuminate (warts)
  • Induces local immuno-response (interferon alpha, beta, gamma, TNF) to decrease viral load
  • Apply 3x weekly for 16 weeks (~50% complete clearance)
  • Keep in mind: recurrence is common
200
Q

What is the Epstein Barr Virus (EBV)?

A
  • Herpes family virus
  • Mono (mononucleosis - infectious EBV)
  • Most people are infected at some point
  • Transmitted through body fluids (Saliva, sharing drinks, kissing, etc)
  • Symptoms:
    • Extreme fatigue
    • Sore throat
    • Spleenomegaly
    • Lymph node enlargement
  • Treatment:
    • Rest, avoid straining if splenomegaly is present
    • Typically resolves in 2-6 weeks
    • No drug treatment to shorten symptoms
201
Q

What is Amantadine?

A
  • MOA - prevents virus from entering host cell
  • Renally excreted, adjustment to dose required
  • Adverse effects: CNS (confusion, insomnia)
  • Used for:
    • Was once used to treat and prevent influenza A
    • Must be started within 48 hours of symptoms
    • May play a small role in treating Parkinson’s Disease, but reserved for advancing symptoms
202
Q

What is Rimantadine?

A
  • MOA - prevents virus from entering host cell
  • Renally excreted, no dose adjustment needed
  • Adverse effects: CNS (confusion, insomnia) - more pronounced with Amantadine
  • Used for:
    • Was once used to treat and prevent influenza A
    • Must be started within 48 hours of symptoms
203
Q

What is Osteltamivir?

A
  • Tamiflu
  • MOA - inhibits neuroaminidase which is required for the release of the virus from the infected cell
  • Taken PO, causes GI side effects, take with food
  • Used for:
    • Prophylaxis and treatment of Influenza type A and B
    • Usually only lessons symptoms by 1 day if taken within 48 hours of start of symptoms
204
Q

What is Zanamivir?

A
  • MOA - inhibits neuroaminidase which is required for the release of the virus from the infected cell
  • Taken as a dry powder delievered by inhalation
    • May cause wheezing and bronchospasm
    • Avoid in patients with COPD/Asthma
  • Used for:
    • Prophylaxis and treatment of Influenza type A and B
    • Usually only lessons symptoms by 1 day if taken within 48 hours of start of symptoms
205
Q

What antivirals for:
Anti-herpetic (4)
Anti-CMV (4)
Anti-influenza (4)

A

Anti-herpetic
* Acyclovir
* Valacyclovir
* Famciclovir
* Penciclovir (topical)

Anti-CMV
* Ganciclovir
* Valganciclovir
* Cidofovir
* Foscarnet

Anti-influenza
* Amantadine
* Rimantadine
* Ostelmavir
* Zanamivir

206
Q
A

Pharmacology - PMC 621 (3 decks)

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