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Respiratory II > CIS: Pharmacotherapy of Respiratory Infections > Flashcards

CIS: Pharmacotherapy of Respiratory Infections Flashcards

1
Q

Site of Antimicrobial Action

A
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2
Q

Translation

A

Translation

Aminoglycosides (30S) & linezolid (50S)

Tetracyclines (30S)

Macrolides (50S) & clindamycin (50S)

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3
Q

Case 1

A 56 y/o male presents to his primary-care provider’s office because of fever, chills, productive cough and confusion for the past 4 days.

Chest X-ray: dense, right lower lobe infiltrate

Most likely infecting pathogen?

A. Haemophilus influenzae

B. Klebsiella pneumoniae

C. Mycoplasma pneumoniae

D. Staphylococcus aureus

E. Streptococcus pneumoniae

A

Case 1

Most likely infecting pathogen?

A. Haemophilus influenzae

B. Klebsiella pneumoniae

C. Mycoplasma pneumoniae

D. Staphylococcus aureus

E. Streptococcus pneumoniae

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4
Q

CAP – Common Infecting Organisms

A
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5
Q

Case 1

A 56 y/o male presents to his primary-care provider’s office because of fever, chills, productive cough and confusion for the past 4 days.

Chest X-ray: dense, right lower lobe infiltrate

Almost all of the major decisions regarding management of CAP resolve around….

A

Case 1

Almost all of the major decisions regarding management of CAP resolve around….

Initial assessment of severity

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6
Q

Case 1

A 56 y/o male presents to his primary-care provider’s office because of fever, chills, productive cough and confusion for the past 4 days.

Chest X-ray: dense, right lower lobe infiltrate

Vital signs: Temp 100 ˚F, BP 140/90 mmHg, HR 100 bpm, RR 28 rpm

CURB-65?

A

Case 1

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7
Q

Case 1

A 56 y/o male presents to his primary-care provider’s office because of fever, chills, productive cough and confusion for the past 4 days.

Chest X-ray: dense, right lower lobe infiltrate

Vital signs: Temp 100 ˚F, BP 140/90 mmHg, HR 100 bpm, RR 28 rpm

Which of the following drugs is most appropriate in the treatment of this patient?

A.Azithromycin

B.Ceftazidime

C.Clindamycin

D.Penicillin G

E.Trimethoprim-sulfamethoxazole

A

Case 1

Which of the following drugs is most appropriate in the treatment of this patient?

A.Azithromycin

B.Ceftazidime

C.Clindamycin

D.Penicillin G

E.Trimethoprim-sulfamethoxazole

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8
Q

CAP – Empiric Antimicrobial Guidelines

Outpatient Recommendations

A

—CAP – Empiric Antimicrobial Guidelines

Outpatient Recommendations

◦Previously healthy

–Macrolide PO (azithromycin, clarithromycin)

-OR-

–Doxycycline PO

◦DRSP risk (comorbidities, age > 65 years, use of antimicrobials within 3 months)

–Respiratory fluoroquinolone PO (levofloxacin, moxifloxacin)

-OR-

–B-lactam PO [high dose amoxicillin or amoxicillin-clavulanate preferred (alternates: ceftriaxone, cefuroxime)] PLUS a macrolide PO

—

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9
Q

Case 1

A 56 y/o male presents to his primary-care provider’s office because of fever, chills, productive cough and confusion for the past 4 days.

Chest X-ray: dense, right lower lobe infiltrate

Vital signs: Temp 100 ˚F, BP 140/90 mmHg, HR 100 bpm, RR 28 rpm

What is the mechanism of action of the drug most appropriate for treatment of this patient?

A.Binds DNA gyrase preventing relaxation of DNA supercoils

B.Blocks protein synthesis by inhibiting translocation

C.Disrupts cell membrane structure

D.Prevents initiation of protein synthesis

E.Prevents the attachment of aminoacyl tRNA to acceptor site

A

Case 1

What is the mechanism of action of the drug most appropriate for treatment of this patient?

A.Binds DNA gyrase preventing relaxation of DNA supercoils

B.Blocks protein synthesis by inhibiting translocation

C.Disrupts cell membrane structure

D.Prevents initiation of protein synthesis

E.Prevents the attachment of aminoacyl tRNA to acceptor site

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10
Q

Case 1

A 56 y/o male presents to his primary-care provider’s office because of fever, chills, productive cough and confusion for the past 4 days.

Chest X-ray: dense, right lower lobe infiltrate

Vital signs: Temp 100 ˚F, BP 140/90 mmHg, HR 100 bpm, RR 28 rpm

Sputum gram stain: abundant neutrophils and gram-positive diplococci

Would this information change your treatment of choice?

A.Azithromycin

B.Ceftazidime

C.Clindamycin

D.Penicillin G

E.Trimethoprim-sulfamethoxazole

A

Case 1

Would this information change your treatment of choice?

A.Azithromycin

B.Ceftazidime

C.Clindamycin

D.Penicillin G

E.Trimethoprim-sulfamethoxazole

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11
Q

Case 1

A 56 y/o male presents to his primary-care provider’s office because of fever, chills, productive cough and confusion for the past 4 days.

Chest X-ray: dense, right lower lobe infiltrate

Vital signs: Temp 100 ˚F, BP 140/90 mmHg, HR 100 bpm, RR 28 rpm

Sputum culture: S. pneumoniae with high-level penicillin resistance

Now which antibiotic would be most appropriate?

A.Azithromycin

B.Cefazolin

C.Doxycycline

D.Levofloxacin

E.Trimethoprim/sulfamethoxazole

A

Case 1

Now which antibiotic would be most appropriate?

A.Azithromycin

B.Cefazolin

C.Doxycycline

D.Levofloxacin

E.Trimethoprim/sulfamethoxazole

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12
Q

Case 1

A 56 y/o male presents to his primary-care provider’s office because of fever, chills, productive cough and confusion for the past 4 days.

Chest X-ray: dense, right lower lobe infiltrate

Vital signs: Temp 100 ˚F, BP 140/90 mmHg, HR 100 bpm, RR 28 rpm

Sputum culture: S. pneumoniae with high-level penicillin resistance

What is the mechanism for penicillin resistance?

A.Alteration of the penicillin-binding protein

B.Beta-lactamase production

C.Efflux pumps

D.Poor penetration

E.Alternation of porin channels

What is the mechanism for penicillin resistance?

A

Case 1

What is the mechanism for penicillin resistance?

A.Alteration of the penicillin-binding protein

B.Beta-lactamase production

C.Efflux pumps

D.Poor penetration

E.Alternation of porin channels

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13
Q

Case 1

A 56 y/o male presents to his primary-care provider’s office because of fever, chills, productive cough and confusion for the past 4 days.

Chest X-ray: dense, right lower lobe infiltrate

Vital signs: Temp 100 ˚F, BP 140/90 mmHg, HR 100 bpm, RR 28 rpm

Sputum culture: S. pneumoniae with high-level penicillin resistance

Which of the following is NOT a risk factor for penicillin-resistant S. pneumoniae?

A.Age > 65 years

B.Alcoholism

C.Antibiotics within the past 3 months

D.Cruise within previous two weeks

E.Multiple medical comorbidities

A

Case 1

Which of the following is NOT a risk factor for penicillin-resistant S. pneumoniae?

A.Age > 65 years

B.Alcoholism

C.Antibiotics within the past 3 months

D.Cruise within previous two weeks

E.Multiple medical comorbidities

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14
Q

CAP – Resistant Organisms

A

CAP – Resistant Organisms

  • —Drug-resistant S. pneumoniae (DRSP)

◦Age < 2 years or > 65 years

◦B-lactam use within previous 3 months

◦Alcoholism

◦Immunosuppressive illness or therapy

◦Exposure to child at day care

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15
Q

Case 2

A 68 y/o female presents to the ED with a two day history of productive cough and fever.

She complains of shortness of breath and sharp pains in her chest when she breathes deeply.

Three weeks ago she was treated with ciprofloxacin for a urinary tract infection.

Demographics: 68 y/o female, 2 day history productive cough/fever.

Ciprofloxacin three weeks ago for a urinary tract infection.

Temp: 101 ˚F, BP 125/75 mmHg, HR 90 bpm, RR 32 rpm,

O2 saturation (RA) 88%

WBC 15,000 cells/mm3, band neutrophils 9%

Chest X-ray: left lower lobe infiltrate

68 y/o female, admit to hospital with community-acquired pneumonia

Ciprofloxacin three weeks ago for a urinary tract infection.

Which of the following regimens is most appropriate?

A.Ceftriaxone

B.Ceftriaxone plus azithromycin

C.Doxycycline

D.Levofloxacin

E.Levofloxacin plus azithromycin

A

Case 2

Which of the following regimens is most appropriate?

A.Ceftriaxone

B.Ceftriaxone plus azithromycin

C.Doxycycline

D.Levofloxacin

E.Levofloxacin plus azithromycin

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16
Q

CAP – Empiric Antimicrobial Guidelines

—Inpatient, Non-Intensive Care Unit Recommendations

A

CAP – Empiric Antimicrobial Guidelines

  • —Inpatient, Non-Intensive Care Unit Recommendations
    • –Respiratory FQ IV or PO (levofloxacin, moxifloxacin)
  • OR-
  • –B-lactam IV (ceftriaxone, cefotaxime, or ampicillin preferred) PLUS macrolide IV (azithromycin)
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17
Q

Case 2

68 y/o female, admit to hospital with community-acquired pneumonia. Ciprofloxacin three weeks ago for a urinary tract infection.

Which of the following parameters is not routinely monitored during antibiotic therapy to determine response?

A.Adverse effects

B.Chest X-ray

C.Fever

D.Respiratory rate

E.WBC count

A

Case 2

Which of the following parameters is not routinely monitored during antibiotic therapy to determine response?

A.Adverse effects

B.Chest X-ray

C.Fever

D.Respiratory rate

E.WBC count

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18
Q

CAP

Signs of clinical improvement:

A

CAP

Signs of clinical improvement:

  • Temperature ≤ 37.8 ˚C
  • HR ≤ 100 bpm
  • RR ≤ 24 breaths/min
  • SBP ≥ 90 mmHg
  • Arterial 02 saturation ≥ 90%
  • Ability to maintain oral intake
  • Normal mental status
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19
Q

Case 2

68 y/o female, admit to hospital with community-acquired pneumonia Ciprofloxacin three weeks ago for a urinary tract infection.

Which of the following antimicrobial regimens does not cover atypical pathogens?

A.Azithromycin

B.Ceftriaxone

C.Doxycycline

D.Levofloxacin plus ceftriaxone

E.Moxifloxacin

A

Case 2

Which of the following antimicrobial regimens does not cover atypical pathogens?

A.Azithromycin

B.Ceftriaxone

C.Doxycycline

D.Levofloxacin plus ceftriaxone

E.Moxifloxacin

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20
Q

Case 2

68 y/o female, admit to hospital with community-acquired pneumonia

Height 5’6”, Weight 135 lbs

SCr 2 mg/dL

Which of the following does NOT need to be dose adjusted if prescribed to our patient?

A.Amoxicillin

B.Ampicillin/sulbactam

C.Ceftriaxone

D.Levofloxacin

E.Ertapenem

A

Case 2

Which of the following does NOT need to be dose adjusted if prescribed to our patient?

A.Amoxicillin

B.Ampicillin/sulbactam

C.Ceftriaxone

D.Levofloxacin

E.Ertapenem

[140 – age (years)] x mass (kg) x (0.85 if female)/ 72 x SCr (mg/dL) = ~26 mL/min

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21
Q

Case 3

A 76 y/o male was admitted to the hospital 13 days ago for coronary artery bypass grafting (CABG).

Post-CABG, patient was recovering slowly and was unable to be extubated.

He developed a fever and became agitated with increasing oxygen demands.

76 y/o male, CABG13 days ago, unable to be extubated

Temp 102.8 ˚F, WBC 23,500 cells/mm3, band neutrophils 20%

SCr 1.2 mg/dL

Two blood cultures: pending

Sputum culture: 4+ WBC and gram-negative bacilli

Diagnosis?

A

Case 3

Diagnosis?

Ventilator-associated pneumonia

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22
Q

Case 3

76 y/o male, CABG13 days ago, unable to be extubated

Temp 102.8 ˚F, WBC 23,500 cells/mm3, band neutrophils 20%

SCr 1.2 mg/dL

Two blood cultures: pending

Sputum culture: 4+ WBC and gram-negative bacilli

What is the most likely infecting pathogen?

A.Bacteroides fragilis

B.Candida albicans

C.Pseudomonas aeruginosa

D.Staphylococcus aureus

E.Streptococcus pneumoniae

A

Case 3

What is the most likely infecting pathogen?

A.Bacteroides fragilis

B.Candida albicans

C.Pseudomonas aeruginosa

D.Staphylococcus aureus

E.Streptococcus pneumoniae

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23
Q

HCAP, HAP & VAP

A

HCAP, HAP & VAP

—Early onset (< 4 days) vs. late onset (5+ days)

—Common pathogens

◦Aerobic gram-negative

–P. aeruginosa

–E. coli

–K. pneumoniae

–Acinetobacter spp.

◦GPCs

–MRSA (more common in diabetes, head trauma, those hospitalized in ICUs)

◦Oropharyngeal commensals

–Viridans group streptococci

–Coagulase-negative staphylococci

–Neisseria spp.

–Corynebacterium spp.

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24
Q

Case 3

76 y/o male, CABG13 days ago, unable to be extubated

Temp 102.8 ˚F, WBC 23,500 cells/mm3, band neutrophils 20%

SCr 1.2 mg/dL

Two blood cultures: pending

Sputum culture: 4+ WBC and gram-negative bacilli

What is the most likely infecting pathogen?

A.Bacteroides fragilis

B.Candida albicans

C.Pseudomonas aeruginosa

D.Staphylococcus aureus

E.Streptococcus pneumoniae

A

Case 3

What is the most likely infecting pathogen?

A.Bacteroides fragilis

B.Candida albicans

C.Pseudomonas aeruginosa

D.Staphylococcus aureus

E.Streptococcus pneumoniae

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25
Q

Case 3

76 y/o male, CABG13 days ago, unable to be extubated

Temp 102.8 ˚F, WBC 23,500 cells/mm3, band neutrophils 20%

SCr 1.2 mg/dL

Two blood cultures: pending

Sputum culture: 4+ WBC and gram-negative bacilli

Which of the following empiric treatment regimens is most appropriate for this patient?

A.Ceftazidime plus gentamicin plus vancomycin

B.Ceftriaxone

C.Levofloxacin plus metronidazole

D.Piperacillin/tazobactam plus gentamicin

E.Vancomycin

A

Case 3

Which of the following empiric treatment regimens is most appropriate for this patient?

A.Ceftazidime plus gentamicin plus vancomycin

B.Ceftriaxone

C.Levofloxacin plus metronidazole

D.Piperacillin/tazobactam plus gentamicin

E.Vancomycin

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26
Q

Empiric Therapy – Late Onset

A

Empiric Therapy – Late Onset

  • —Potential pathogens (MDR):

◦P. aeruginosa

◦K. pneumoniae (ESBL+)

◦Acinetobacter

◦MRSA

  • —Treatment:

◦Antipseudomonal cephalosporin (cefepime, ceftazidime) OR antipseudomonal carbapenem (imipenem, meropenem) OR B-lactam/B-lactamase inhibitor (piperacillin-tazobactam)

PLUS

◦Antipseudomonal FQ (ciprofloxacin, levofloxacin) OR aminoglycoside (gentamicin, tobramycin)

PLUS

◦Linezolid OR vancomycin

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27
Q

Case 3

76 y/o male, CABG13 days ago, unable to be extubated

Temp 102.8 ˚F, WBC 23,500 cells/mm3, band neutrophils 20%

SCr 1.2 mg/dL

Two blood cultures: pending

Sputum culture: 4+ WBC and gram-negative bacilli

Your attending would like to use meropenem. Which class of antimicrobials does meropenem belong to?

A.Carbapenems

B.Fluoroquinolones

C.Monobactams

D.Penicillins

E.Tetracyclines

A

Case 3

Your attending would like to use meropenem. Which class of antimicrobials does meropenem belong to?

A.Carbapenems

B.Fluoroquinolones

C.Monobactams

D.Penicillins

E.Tetracyclines

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28
Q

Case 4

A 55 y/o male presents to the ED with a 6-hour history of a bloody nose. He says he has been unable to stop the bleeding.

PE: multiple bruises on lower legs and forearms.

PMH: significant for atrial fibrillation

INR 5.8

You ask if he has taken any other medications and he says he was recently prescribed an antibiotic for pneumonia.

Which of the following best describes the mechanism of action of the antibiotic most likely prescribed?

A.Binds the 50S ribosomal subunit

B.Blocks attachment of aminoacyl-tRNA to the A site

C.Causes misreading of mRNA information

D.Inhibits folate synthesis

E.Inhibits mycolic acid synthesis

A

Case 4

Which of the following best describes the mechanism of action of the antibiotic most likely prescribed?

A.Binds the 50S ribosomal subunit

B.Blocks attachment of aminoacyl-tRNA to the A site

C.Causes misreading of mRNA information

D.Inhibits folate synthesis

E.Inhibits mycolic acid synthesis

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29
Q

Case 5

A 25 y/o female presents to the hospital for a CF “tune-up” as she has had increasing yellow-green sputum production, shortness of breath, and post-tussive emesis.

She complains of a decreased appetite and a 2.8 kg weight loss since her previous clinic visit.

A

Case 5

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30
Q

Cystic Fibrosis and Lung Health

A
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31
Q

Prevalence of Bacteria Identified in Respiratory Secretions from pts. w/Cystic FIbrosis

A
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32
Q

Case 5

Pseudomonas aeruginosa

A

Case 5

Pseudomonas aeruginosa

  • Aztreonam = S
  • Cefepime = S
  • Ceftazidime = S
  • Ciprofloxacin = R
  • Imipenem = S
  • Levofloxacin = R
  • Meropenem = S
  • Piperacillin/tazobactam = S
  • Tobramycin = S
  • Amikacin = I
    *
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33
Q

Case 5

Staphylococcus aureus

A

Case 5

Staphylococcus aureus

  • Cefazolin = R
  • Ceftriaxone = R
  • Clindamycin= S
  • Erythromycin = R
  • Linezolid = S
  • Oxacillin = R
  • TMP/SMX = S
  • Vancomycin = S
34
Q

Case 5

A 25 y/o female, with cystic fibrosis, admitted to the hospital with an acute pulmonary exacerbation

What is the likely mechanism of resistance of Staphylococcus aureus?

A.Alternation of porin channels

B.Beta-lactamase production

C.Efflux pumps

D.Poor penetration

E.Reduced affinity of penicillin-binding proteins

A

Case 5

What is the likely mechanism of resistance of Staphylococcus aureus?

A.Alternation of porin channels

B.Beta-lactamase production

C.Efflux pumps

D.Poor penetration

E.Reduced affinity of penicillin-binding proteins

Remember

Staphylococcus aureus

Cefazolin = R

Ceftriaxone = R

Clindamycin = S

Erythromycin = R

Linezolid = S

Oxacillin= R

TMP/SMX = S

Vancomycin = S

35
Q

Case 5

A 25 y/o female, with cystic fibrosis, admitted to the hospital with an acute pulmonary exacerbation

What is the likely mechanism of resistance of Pseudomonas aeruginosa?

A.Alternation of porin channels

B.Beta-lactamase production

C.Efflux pumps

D.Poor penetration

E.Reduced affinity of penicillin-binding proteins

A

Case 5

What is the likely mechanism of resistance of Pseudomonas aeruginosa?

A.Alternation of porin channels

B.Beta-lactamase production

C.Efflux pumps

D.Poor penetration

E.Reduced affinity of penicillin-binding proteins

Pseudomonas aeruginosa

Aztreonam = S

Cefepime = S

Ceftazidime = S

Ciprofloxacin = R

Imipenem = S

Levofloxacin = R

Meropenem = S

Piperacillin/tazobactam = S

Tobramycin = S

Amikacin = I

36
Q

Case 5

A 25 y/o female, with cystic fibrosis, admitted to the hospital with an acute pulmonary exacerbation

When this patient experiences another CF exacerbation, which is the most appropriate intravenous antibiotic regimen for empiric management (based on most recent sputum culture)?

A.Meropenem plus ceftazidime

B.Tobramycin

C.Tobramycin + piperacillin/tazobactam

D.Tobramycin + piperacillin/tazobactam + vancomycin

E.Vancomycin

A

Case 5

When this patient experiences another CF exacerbation, which is the most appropriate intravenous antibiotic regimen for empiric management (based on most recent sputum culture)?

A.Meropenem plus ceftazidime

B.Tobramycin

C.Tobramycin + piperacillin/tazobactam

D.Tobramycin + piperacillin/tazobactam + vancomycin

E.Vancomycin

37
Q

Case 5

A 25 y/o female, with cystic fibrosis, admitted to the hospital with an acute pulmonary exacerbation

What is the purpose of tazobactam in the antibiotic combination piperacillin/tazobactam?

A.To increase the absorption of piperacillin

B.To inhibit the bacterial enzyme that inactivates piperacillin

C.To prevent alteration of the penicillin-binding protein

D.To reduce the adverse effects of piperacillin

E.It is another antibiotic

A

Case 5

What is the purpose of tazobactam in the antibiotic combination piperacillin/tazobactam?

A.To increase the absorption of piperacillin

B.To inhibit the bacterial enzyme that inactivates piperacillin

C.To prevent alteration of the penicillin-binding protein

D.To reduce the adverse effects of piperacillin

E.It is another antibiotic

38
Q

Case 5

A 25 y/o female, with cystic fibrosis, admitted to the hospital with an acute pulmonary exacerbation

Our patient continues to culture Pseudomonas aeruginosa on subsequent sputum cultures. What maintenance therapy may be initiated that acts as an anti-inflammatory and may decrease the virulence of Pseudomonas aeruginosa?

A.Azithromycin

B.Hypertonic saline

C.Inhaled fluticasone

D.Prednisone

E.Tobramycin inhaled (TOBI)

A

Case 5

Our patient continues to culture Pseudomonas aeruginosa on subsequent sputum cultures. What maintenance therapy may be initiated that acts as an anti-inflammatory and may decrease the virulence of Pseudomonas aeruginosa?

A.Azithromycin

B.Hypertonic saline

C.Inhaled fluticasone

D.Prednisone

E.Tobramycin inhaled (TOBI)

39
Q

Case 6

An 8 y/o female presents with recent onset of fever, cough, and chills. Community-acquired pneumonia is suspected. She is to be treated as an outpatient.

Which of the following should NOT be used to treat this patient?

A.Amoxicillin

B.Azithromycin

C.Cefotaxime

D.Doxycycline

E.Levofloxacin

A

Case 6

Which of the following should NOT be used to treat this patient?

A.Amoxicillin – OK

B.Azithromycin – OK

C.Cefotaxime – IV only 3rd generation cephalosporin

D.Doxycycline – NO – teeth discoloration/impaired bone development

E.Levofloxacin – NO – not approved for < 16 years, cartilage damage

40
Q

Case 7

An 85 y/o female is brought to the ED, by her daughter, due to fever (101 ˚F), productive cough, and shortness of breath.

Her daughter is concerned because her mother has not been tolerating solid foods recently. She may have choked several days ago.

BP: 116/85, RR: 32 breaths/minute

Chest X-ray: right lower lobe infiltrate

An 85 y/o female, admitted to the general medical floor with aspiration pneumonia

You would like to use a B-lactam + azithromycin to follow the CAP guidelines. Which B-lactam has anaerobic activity?

A.Ampicillin/sulbactam

B.Cefotaxime

C.Ceftriaxone

D.Ceftazidime

E.Nafcillin

A

Case 7

You would like to use a B-lactam + azithromycin to follow the CAP guidelines. Which B-lactam has anaerobic activity?

A.Ampicillin/sulbactam

B.Cefotaxime

C.Ceftriaxone

D.Ceftazidime

E.Nafcillin

41
Q

Case 7

An 85 y/o female, admitted to the general medical floor with aspiration pneumonia

Which protein synthesis inhibitor has anaerobic activity and is used to treat aspiration pneumonia?

A.Ceftriaxone

B.Clindamycin

C.Daptomycin

D.Gentamicin

E.Metronidazole

A

Case 7

Which protein synthesis inhibitor has anaerobic activity and is used to treat aspiration pneumonia?

A.Ceftriaxone

B.Clindamycin

C.Daptomycin

D.Gentamicin

E.Metronidazole

42
Q

Case 8

A 47 y/o male with severe RA has been maintained on daily prednisone for the past 6 years. He recently moved to Denver from the St. Louis area where he raised chickens.

For the past 4 weeks, he has experienced daily fevers, drenching night sweats, anorexia, and a 16 lb weight loss.

He is admitted to the hospital.

Chest X-ray: bilateral interstitial infiltrates

Diagnosis?

A

Case 8

Diagnosis?

Histoplasma capsulatum

43
Q

Case 8

A 47 y/o male with severe RA has been maintained on daily prednisone for the past 6 years. He recently moved to Denver from the St. Louis area where he raised chickens.

For the past 4 weeks, he has experienced daily fevers, drenching night sweats, anorexia, and a 16 lb weight loss.

He is admitted to the hospital.

Chest X-ray: bilateral interstitial infiltrates

His PCP would like to prescribe itraconazole. What is the mechanism of action of the azole antifungals?

A.Formation of pores within fungal cell wall

B.Inhibition of B(1,3)-glucan synthesis

C.Inhibition of ergosterol synthesis

A

Case 8

His PCP would like to prescribe itraconazole. What is the mechanism of action of the azole antifungals?

A.Formation of pores within fungal cell wall

B.Inhibition of B(1,3)-glucan synthesis

C.Inhibition of ergosterol synthesis

44
Q

Antifungal Mechanisms of Action

A
45
Q

Antifungal Spectrum

A
46
Q

Case 9

A 48 y/o neutropenic, female is recovering in the oncology unit status post hematopoietic cell transplant (HCT).

She develops symptoms of fever, pleuritic chest pain, and hemoptysis.

Diagnosis: invasive pulmonary aspergillosis

Her oncologist would like to begin voriconazole.

What specific adverse drug reaction is associated with use of voriconazole as opposed to other azole antifungals?

A

Case 9

Her oncologist would like to begin voriconazole.

What specific adverse drug reaction is associated with use of voriconazole as opposed to other azole antifungals?

Visual changes

47
Q

Case 10

A 35-yo woman presents with a persistent cough following an acute respiratory viral infection that began 7 days ago.

Although the nasal stuffiness and sore throat resolved 3-4 days ago, the cough has persisted and her sputum has become thick and mucoid; a burning, substernal pain is associated with each coughing episode.

Course rales and rhonchi are heard on physical exam of her chest. She is afebrile.

HR 75 bpm, BP 132/92 mmHg, RR 22 rpm.

She is a non-smoker.

What is the diagnosis?

Which of the following is an appropriate treatment for this woman?

A.Azithromycin

B.Clindamycin

C.Levofloxacin

D.Doxycycline

E.Codeine

A

Case 10

What is the diagnosis?

acute bronchitis

Which of the following is an appropriate treatment for this woman?

A.Azithromycin

B.Clindamycin

C.Levofloxacin

D.Doxycycline

E.Codeine

48
Q

Drug List

—First-line agents and related second-line agents for TB

A

First-line agents and related second-line agents for TB

◦Isoniazid

–Ethionamide

◦Rifampin

–Rifabutin

–Rifapentine

◦Pyrazinamide

◦Ethambutol

◦Streptomycin

–Amikacin

–Capreomycin

–Kanamycin

49
Q

Drug List

—Additional second-line (and third-line) agents for TB

A

Drug List

—Additional second-line (and third-line) agents for TB

◦Fluoroquinolones

◦Aminosalicylic acid

◦Cycloserine

◦Linezolid

50
Q

Case 1

A 36 y/o female presents with a 2-month history of cough, which has recently become productive, and an unexplained 15 pound weight loss. Additional symptoms include fatigue and night sweats.

Physical examination is unremarkable.

Chest X-ray: pulmonary infiltrates.

—

PMH: well-controlled type-1 diabetes mellitus and poor nutritional status secondary to frequent dieting.

She works as a volunteer in a nursing home several days a week where it was recently discovered that two patients who she had been caring for had undiagnosed active tuberculosis.

—

Tests ordered

  • Tuberculin purified protein derivative (PPD) skin test
  • Palpable induration of 14 mm, read at 48 hours
  • Sputum collections for susceptibility testing of cultures
  • Results back in 2-4 weeks
  • Sputum acid-fast bacillus (AFB) smear
  • Positive for AFB

36 y/o female with active tuberculosis

Well-controlled type-1 diabetes mellitus

Poor nutritional status secondary to frequent dieting

The most active drug for the treatment of TB caused by susceptible strains is prescribed. What is the mechanism of action?

Inhibition of:

A.CYP450 3A4.

B.DNA gyrase.

C.folate synthesis.

D.mycolic acid synthesis.

E.the best agent has an unknown MOA.

Which first-line agent was prescribed?

A

Case 1

The most active drug for the treatment of TB caused by susceptible strains is prescribed. What is the mechanism of action?

Inhibition of:

A.CYP450 3A4.

B.DNA gyrase.

C.folate synthesis.

D.mycolic acid synthesis.

E.the best agent has an unknown MOA.

Which first-line agent was prescribed?

Isoniazid (INH)

51
Q

Isoniazid (INH)

A

Isoniazid (INH)

—MOA: inhibits synthesis of mycolic acids

◦Prodrug, activated by KatG

◦Active form binds AcpM and KasA à inhibits mycolic acid synthesis

—

—Resistance:

◦Mutation or deletion of katG gene

◦Overexpression of inhA and ahpC

◦Mutation in kasA

52
Q

Mycobacteria vs. Gram-Positive vs. Gram-Negative

A
53
Q

Case 1

36 y/o female with active tuberculosis

Well-controlled type-1 diabetes mellitus

Poor nutritional status secondary to frequent dieting

Which agent, or combination of agents, is most recommended for this patient?

  • A. Isoniazid
  • B. Isoniazid, Rifampin
  • C. Isoniazid, Rifampin, Pyrazinamide
  • D. Isoniazid, Rifampin, Pyrazinamide, Ethambutol
  • E. Isoniazid, Rifampin, Pyrazinamide, Ethambutol, Streptomycin
A

Case 1

Which agent, or combination of agents, is most recommended for this patient?

  • A. Isoniazid
  • B. Isoniazid, Rifampin
  • C. Isoniazid, Rifampin, Pyrazinamide
  • D. Isoniazid, Rifampin, Pyrazinamide, Ethambutol
  • E. Isoniazid, Rifampin, Pyrazinamide, Ethambutol, Streptomycin
54
Q

Case 1

36 y/o female with active tuberculosis

Well-controlled type-1 diabetes mellitus

Poor nutritional status secondary to frequent dieting

Why is it important to use a combination drug regimen?

A

Case 1

Why is it important to use a combination drug regimen?

—2+ active agents should always be used for active TB to prevent resistance

55
Q

Combination Drug Therapy

A

Combination Drug Therapy

  • —Drug resistant mutants – 1 bacillus in 106

◦Asymptomatic patients – bacillary load of 103

◦Cavitary pulmonary TB – bacillary load > 108

  • –Resistance readily selected out if single drug used

——

  • Combination therapy, drug resistance – 1 bacillus in 1012

◦Rates of resistance additive functions of individual rates

◦Example: only 1 in 1013 organisms would be naturally resistant to both isoniazid (1 in 106) and rifampin (1 in 107)

—

  • —2+ active agents should always be used for active TB to prevent resistance
56
Q

Case 1

36 y/o female with active tuberculosis

Well-controlled type-1 diabetes mellitus

Poor nutritional status secondary to frequent dieting

Why isn’t streptomycin included in this regimen?

A

Case 1

Why isn’t streptomycin included in this regimen?

—Therapeutic Use:

◦When injectable drug needed/desired – patients with severe, life-threatening forms of TB

57
Q

Streptomycin

A

Streptomycin

  • MOA: irreversible inhibitor of protein synthesis
    • Binds S12 ribosomal protein of 30S subunit
  • Resistance:
    • Mutations in rpsL or rrs gene which alter binding site
  • Therapeutic Use:
    • When injectable drug needed/desired – patients with severe, life-threatening forms of TB
  • ADRs:
    • Ototoxicity (vertigo and hearing loss)
    • Nephrotoxicity
    • Relatively contraindicated in pregnancy (newborn deafness)
  • Related Second-Line Agents: capreomycin, kanamycin, amikacin
58
Q

Case 1

36 y/o female with active tuberculosis

Well-controlled type-1 diabetes mellitus

Poor nutritional status secondary to frequent dieting

Results from the drug-susceptibility testing show that there are tubercle bacilli resistant to one agent in the current regimen. Isolates with mutations in the gene encoding arabinosyl transferase (emb gene) have been identified. Which agent is ineffective?

A.Ethambutol

B.Isoniazid

C.Pyrazinamide

D.Rifampin

E.Streptomycin

A

Case 1

Results from the drug-susceptibility testing show that there are tubercle bacilli resistant to one agent in the current regimen. Isolates with mutations in the gene encoding arabinosyl transferase (emb gene) have been identified. Which agent is ineffective?

A.Ethambutol

B.Isoniazid

C.Pyrazinamide

D.Rifampin

E.Streptomycin

59
Q

Case 1

36 y/o female with active tuberculosis

Well-controlled type-1 diabetes mellitus

Poor nutritional status secondary to frequent dieting

What change(s) should be made to the current regimen?

A

Case 1

What change(s) should be made to the current regimen?

—ADRs:

◦Retrobulbar neuritis (loss of visual acuity, red-green color blindness)

◦Rash

◦Drug fever

◦Relatively contraindicated in children too young to assess visual acuity

◦

60
Q

Ethambutol (EMB)

A

Ethambutol (EMB)

  • MOA: disrupts synthesis of arabinoglycan
    • Inhibits mycobacterial arabinosyl transferases (encoded by embCAB operon)
  • Resistance:
    • Overexpression of emb gene products
    • Mutation in embB gene
  • ADRs:
    • Retrobulbar neuritis (loss of visual acuity, red-green color blindness)
    • Rash
    • Drug fever
    • Relatively contraindicated in children too young to assess visual acuity
61
Q

Case 1

36 y/o female with active tuberculosis

Well-controlled type-1 diabetes mellitus

Poor nutritional status secondary to frequent dieting

The patient returns for follow-up one month after starting the 4 drug regimen. Which of the following lab values is most likely elevated?

A.Creatine phosphokinase

B.Hematocrit

C.Potassium

D.Serum aminotransferase activity

E.Triglycerides

A

Case 1

The patient returns for follow-up one month after starting the 4 drug regimen. Which of the following lab values is most likely elevated?

A.Creatine phosphokinase

B.Hematocrit

C.Potassium

D.Serum aminotransferase activity

E.Triglycerides

62
Q

Case 1

36 y/o female with active tuberculosis

Well-controlled type-1 diabetes mellitus

Poor nutritional status secondary to frequent dieting

Which agent is most likely to cause hepatotoxicity in this patient?

A.Ethambutol

B.Isoniazid

C.Pyrazinamide

D.Rifampin

E.Streptomycin

A

Case 1

Which agent is most likely to cause hepatotoxicity in this patient?

A.Ethambutol

B.Isoniazid

C.Pyrazinamide

D.Rifampin

E.Streptomycin

63
Q

Pyrazinamide (PZA)

—

A

Pyrazinamide (PZA)

  • —MOA: disrupts mycobacterial cell membrane synthesis and transport functions

◦Macrophage uptake, conversion to pyrazinoic acid (POA-)

◦Efflux pump to extracellular milieu

◦POA- protonated to POAH, reenters bacillus

  • —Resistance:

◦Impaired biotransformation, mutation in pncA

  • —ADRs:

◦Hepatotoxicity (1-5%)

◦GI upset

◦Hyperuricemia

64
Q

Drug-induced Hepatitis

A

Drug-induced Hepatitis

  • —The most common major side effect of isoniazid; can also occur with rifampin; pyrazinamide is probably the most hepatotoxic anti-TB agent
  • —Liver aminotransferases may increase up to 3-4 times normal

◦Patients are typically asymptomatic; continue therapy

  • —Clinical hepatitis (with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain) occurs in 1% of isoniazid recipients

◦May be fatal if not promptly discontinued

  • —Risk is age dependent:

< 20 rare

21-35 0.3%

36-50 1.2%

> 50 2.3%

  • —Hepatitis risk increases in patients who are alcoholics and possibly during pregnancy and the postpartum period
65
Q

INH Biotransformation

A

INH Biotransformation

66
Q

Case 1

36 y/o female with active tuberculosis

Well-controlled type-1 diabetes mellitus

Poor nutritional status secondary to frequent dieting

During the follow-up exam, the patient reports frequent tingling and burning in her hands and feet as well as general muscle aches and weakness. What vitamin supplement should be prescribed to alleviate these symptoms?

A.Vitamin A

B.Vitamin B1

C.Vitamin B6

D.Vitamin C

E.Vitamin D

A

Case 1

During the follow-up exam, the patient reports frequent tingling and burning in her hands and feet as well as general muscle aches and weakness. What vitamin supplement should be prescribed to alleviate these symptoms?

A.Vitamin A

B.Vitamin B1

C.Vitamin B6

D.Vitamin C

E.Vitamin D

67
Q

Case 1

36 y/o female with active tuberculosis

Well-controlled type-1 diabetes mellitus

Poor nutritional status secondary to frequent dieting

What about her initial exam would suggest increased risk of peripheral neuropathy?

A

Case 1

What about her initial exam would suggest increased risk of peripheral neuropathy?

68
Q

Case 2

An HIV-infected 38 y/o female with a history of IV drug and alcohol use presents with fevers, drenching night sweats, a poor appetite, and a 20-lb weight loss over the past 4 months. Her current medications include protease inhibitors (part of ART regimen).

Lab values include the following:

—

HCT 23% (normal 36-44%)

CD4 25 cells/mm3

Aspartate transferase 95 IU/L (normal 0-35)

Alanine aminotransferase 135 IU/L (normal 0-35)

Why are we talking about an HIV patient?

—

A

Case 2

Why are we talking about an HIV patient?

69
Q

Case 2

An HIV-infected 38 y/o female with a history of IV drug and alcohol use presents with fevers, drenching night sweats, a poor appetite, and a 20-lb weight loss over the past 4 months. Her current medications include protease inhibitors (part of ART regimen).

Lab values include the following:

—

HCT 23% (normal 36-44%)

CD4 25 cells/mm3

Aspartate transferase 95 IU/L (normal 0-35)

Alanine aminotransferase 135 IU/L (normal 0-35)

What are some important considerations before choosing an anti-TB regimen?

—

A

Case 2

What are some important considerations before choosing an anti-TB regimen?

70
Q

P450 Induction by Rifamycins

A

P450 Induction by Rifamycins

  • —Rifampin is a strong P450 inducer (1A2, 2C9, 2C19, 2D6, 3A4)

◦Use with caution in patients with HIV who are taking protease inhibitors (PIs) and non-nucleoside reverse-transcriptase inhibitors (NNRTIs)

◦Half-lives, and thus efficacy, of agents metabolized by CYP450s (e.g., PIs, NNRTIs) are reduced

◦Other agents metabolized by P450s: isoniazid, digoxin, propranolol, warfarin, oral contraceptives, etc.

  • —Rifampin is the most potent P450 inducer
  • —Rifabutin is the least potent
71
Q

Rifampin (RIF)

A

Rifampin (RIF)

  • —MOA: inhibits RNA synthesis

◦Binds B-subunit of DNA-dependent RNA polymerase (rpoB)

—

  • —Resistance:

◦Reduced binding affinity to RNA polymerase → point mutations within rpoB gene

Related Second-Line Agents: rifapentine, rifabutin

72
Q

Rifampin (RIF)

—ADRs:

A

Rifampin (RIF)

—ADRs:

◦Nausea/vomiting (1.5%)

◦Rash (0.8%)

◦Fever (0.5%)

◦Harmless red/orange color to secretions

◦Hepatotoxicity

◦Flu-like syndrome (20%) in those treated < 2x/week

73
Q

β-Lactam
Mechanism of Action

A

β-Lactam
Mechanism of Action

Time-dependent; structural analogs of D-Ala-D-Ala; covalently bind penicillin-binding proteins (PBPs), inhibit transpeptidation

74
Q

β-Lactam
ADRs

A

β-Lactam
ADRs

  • Penicillins
  • Allergic reactions (0.7-10%)
  • Anaphylaxis (0.004-0.04%)
  • Nausea, vomiting, mild to severe diarrhea
  • Pseudomembranous colitis
  • Cephalosporins
  • 1% risk of cross-reactivity to penicillins
  • Diarrhea
  • Carbapenems
  • Nausea/vomiting (1-20%)
  • Seizures (1.5%)
  • Hypersensitivity
75
Q

Vancomycin
Mechanism of Action

A

Vancomycin
Mechanism of Action

Inhibits cell wall synthesis binding with high affinity to D-Ala-D-Ala terminal of cell wall precursor units

76
Q

Vancomycin
ADRs

A

Vancomycin
ADRs

  • Macular skin rash, chills, fever, rash
  • Red-man syndrome (histamine release): extreme flushing, tachycardia, hypotension
  • Ototoxicity, nephrotoxicity (33% with initial trough > 20 mcg/mL)
77
Q

Fluoroquinolone
Mechanism of Action

A

Fluoroquinolone
Mechanism of Action

Concentration-dependent, targets bacterial DNA gyrase & topoisomerase IV. Prevents relaxation of positive supercoils

78
Q

Fluoroquinolone
ADRs

A

Fluoroquinolone
ADRs

  • GI 3-17% (mild nausea, vomiting, abdominal discomfort)
  • CNS 0.9-11% (mild headache, dizziness, delirium, rare hallucinations)
  • Rash, photosensitivity, Achilles tendon rupture (CI in children)
79
Q

Protein Synthesis Inhibitors
Mechanisms of Action

A

Protein Synthesis Inhibitors
Mechanisms of Action

  • Aminoglycosides (30S)
  • Interferes with initiation
  • Causes misreading & aberrant proteins
  • Tetracyclines (30S)
  • Blocks aminoacyl tRNA acceptor site
  • Macrolides (50S)
  • Inhibits translocation
  • Clindamycin (50S)
  • Inhibits translocation
  • Linezolid (50S)
  • Blocks formation of initiation complex
80
Q
A
81
Q

Protein Synthesis Inhibitors
ADRs

A

Protein Synthesis Inhibitors
ADRs

  • Aminoglycosides (30S)
  • Ototoxicity, nephrotoxicity, neuromuscular block and apnea
  • Tetracyclines (30S)
  • GI, superinfections of C. difficile, photosensitivity, teeth discoloration
  • Macrolides (50S)
  • GI, hepatotoxicity, arrhythmia
  • Clindamycin (50S)
  • GI diarrhea, pseudomembranous colitis, skin rashes
  • Linezolid (50S)
  • Myelosuppression, headache, rash

Respiratory II (14 decks)

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