CIS: Pharmacotherapy of Respiratory Infections

Question 1

Site of Antimicrobial Action

Answer 1

Question 2

Translation

Answer 2

Translation

Aminoglycosides (30S) & linezolid (50S)

Tetracyclines (30S)

Macrolides (50S) & clindamycin (50S)

Question 3

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

Answer 3

Case 1

Most likely infecting pathogen?

A. Haemophilus influenzae

B. Klebsiella pneumoniae

C. Mycoplasma pneumoniae

D. Staphylococcus aureus

E. Streptococcus pneumoniae

Question 4

CAP – Common Infecting Organisms

Answer 4

Question 5

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….

Answer 5

Case 1

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

Initial assessment of severity

Question 6

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?

Answer 6

Case 1

Question 7

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

Answer 7

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

Question 8

CAP – Empiric Antimicrobial Guidelines

Outpatient Recommendations

Answer 8

—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

—

Question 9

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

Answer 9

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

Question 10

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

Answer 10

Case 1

Would this information change your treatment of choice?

A.Azithromycin

B.Ceftazidime

C.Clindamycin

D.Penicillin G

E.Trimethoprim-sulfamethoxazole

Question 11

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

Answer 11

Case 1

Now which antibiotic would be most appropriate?

A.Azithromycin

B.Cefazolin

C.Doxycycline

D.Levofloxacin

E.Trimethoprim/sulfamethoxazole

Question 12

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?

Answer 12

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

Question 13

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

Answer 13

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

Question 14

CAP – Resistant Organisms

Answer 14

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

Question 15

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

Answer 15

Case 2

Which of the following regimens is most appropriate?

A.Ceftriaxone

B.Ceftriaxone plus azithromycin

C.Doxycycline

D.Levofloxacin

E.Levofloxacin plus azithromycin

Question 16

CAP – Empiric Antimicrobial Guidelines

—Inpatient, Non-Intensive Care Unit Recommendations

Answer 16

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)

Question 17

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

Answer 17

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

Question 18

CAP

Signs of clinical improvement:

Answer 18

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

Question 19

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

Answer 19

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

Question 20

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

Answer 20

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

Question 21

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?

Answer 21

Case 3

Diagnosis?

Ventilator-associated pneumonia

Question 22

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

Answer 22

Case 3

What is the most likely infecting pathogen?

A.Bacteroides fragilis

B.Candida albicans

C.Pseudomonas aeruginosa

D.Staphylococcus aureus

E.Streptococcus pneumoniae

Question 23

HCAP, HAP & VAP

Answer 23

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.

Question 24

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

Answer 24

Case 3

What is the most likely infecting pathogen?

A.Bacteroides fragilis

B.Candida albicans

C.Pseudomonas aeruginosa

D.Staphylococcus aureus

E.Streptococcus pneumoniae

Question 25

Case 3 ## Footnote 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

Answer 25

Case 3 ## Footnote 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

Question 26

Empiric Therapy – Late Onset

Answer 26

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

Question 27

Case 3 ## Footnote 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

Answer 27

Case 3 ## Footnote 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

Question 28

Case 4 ## Footnote 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

Answer 28

Case 4 ## Footnote 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

Question 29

Case 5 ## Footnote 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.

Answer 29

Case 5

Question 30

Cystic Fibrosis and Lung Health

Answer 30

Question 31

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

Answer 31

Question 32

Case 5 Pseudomonas aeruginosa

Answer 32

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 *

Question 33

Case 5 Staphylococcus aureus

Answer 33

Case 5 Staphylococcus aureus * Cefazolin = R * Ceftriaxone = R * Clindamycin= S * Erythromycin = R * Linezolid = S * Oxacillin = R * TMP/SMX = S * Vancomycin = S

Question 34

Case 5 ## Footnote 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

Answer 34

Case 5 ## Footnote 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_**

Question 35

Case 5 ## Footnote 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

Answer 35

Case 5 ## Footnote 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

Question 36

Case 5 ## Footnote 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

Answer 36

Case 5 ## Footnote 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

Question 37

Case 5 ## Footnote 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

Answer 37

Case 5 ## Footnote 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

Question 38

Case 5 ## Footnote 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)

Answer 38

Case 5 ## Footnote 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)

Question 39

Case 6 ## Footnote 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

Answer 39

Case 6 ## Footnote 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_**

Question 40

Case 7 ## Footnote 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

Answer 40

Case 7 ## Footnote 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

Question 41

Case 7 ## Footnote 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

Answer 41

Case 7 ## Footnote Which protein synthesis inhibitor has anaerobic activity and is used to treat aspiration pneumonia? A.Ceftriaxone **_B.Clindamycin_** C.Daptomycin D.Gentamicin E.Metronidazole

Question 42

Case 8 ## Footnote 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?

Answer 42

Case 8 ## Footnote Diagnosis? Histoplasma capsulatum

Question 43

Case 8 ## Footnote 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

Answer 43

Case 8 ## Footnote 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_**

Question 44

Antifungal Mechanisms of Action

Answer 44

Question 45

Antifungal Spectrum

Answer 45

Question 46

Case 9 ## Footnote 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?

Answer 46

Case 9 ## Footnote 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

Question 47

Case 10 ## Footnote 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

Answer 47

Case 10 ## Footnote 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_**

Question 48

Drug List ## Footnote —First-line agents and related second-line agents for TB

Answer 48

First-line agents and related second-line agents for TB ## Footnote ◦Isoniazid –Ethionamide ◦Rifampin –Rifabutin –Rifapentine ◦Pyrazinamide ◦Ethambutol ◦Streptomycin –Amikacin –Capreomycin –Kanamycin

Question 49

Drug List ## Footnote —Additional second-line (and third-line) agents for TB

Answer 49

Drug List ## Footnote —Additional second-line (and third-line) agents for TB ◦Fluoroquinolones ◦Aminosalicylic acid ◦Cycloserine ◦Linezolid

Question 50

Case 1 ## Footnote 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?

Answer 50

Case 1 **T**he 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)

Question 51

Isoniazid (INH)

Answer 51

Isoniazid (INH) ## Footnote —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

Question 52

Mycobacteria vs. Gram-Positive vs. Gram-Negative

Answer 52

Question 53

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

Answer 53

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

Question 54

Case 1 ## Footnote 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?

Answer 54

Case 1 ## Footnote Why is it important to use a combination drug regimen? **—2+ active agents should always be used for active TB to prevent resistance**

Question 55

Combination Drug Therapy

Answer 55

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**

Question 56

Case 1 ## Footnote 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?

Answer 56

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**

Question 57

Streptomycin

Answer 57

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

Question 58

Case 1 ## Footnote 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

Answer 58

Case 1 ## Footnote 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

Question 59

Case 1 ## Footnote 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?

Answer 59

Case 1 ## Footnote 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 ◦

Question 60

Ethambutol (EMB)

Answer 60

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

Question 61

Case 1 ## Footnote 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

Answer 61

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

Question 62

Case 1 ## Footnote 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

Answer 62

Case 1 ## Footnote Which agent is most likely to cause hepatotoxicity in this patient? A.Ethambutol B.Isoniazid **_C.Pyrazinamide_** D.Rifampin E.Streptomycin

Question 63

Pyrazinamide (PZA) ## Footnote —

Answer 63

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

Question 64

Drug-induced Hepatitis

Answer 64

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

Question 65

INH Biotransformation

Answer 65

INH Biotransformation

Question 66

Case 1 ## Footnote 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

Answer 66

Case 1 ## Footnote 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

Question 67

Case 1 ## Footnote 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?

Answer 67

Case 1 ## Footnote What about her initial exam would suggest increased risk of peripheral neuropathy?

Question 68

Case 2 ## Footnote 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? —

Answer 68

Case 2 ## Footnote Why are we talking about an HIV patient?

Question 69

Case 2 ## Footnote 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? —

Answer 69

Case 2 ## Footnote What are some important considerations before choosing an anti-TB regimen?

Question 70

P450 Induction by Rifamycins

Answer 70

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

Question 71

Rifampin (RIF)

Answer 71

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

Question 72

Rifampin (RIF) —ADRs:

Answer 72

Rifampin (RIF) ## Footnote —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

Question 73

β-Lactam Mechanism of Action

Answer 73

β-Lactam Mechanism of Action ## Footnote Time-dependent; structural analogs of D-Ala-D-Ala; covalently bind penicillin-binding proteins (PBPs), inhibit transpeptidation

Question 74

β-Lactam ADRs

Answer 74

β-Lactam ADRs ## Footnote * 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

Question 75

Vancomycin Mechanism of Action

Answer 75

Vancomycin Mechanism of Action ## Footnote Inhibits cell wall synthesis binding with high affinity to D-Ala-D-Ala terminal of cell wall precursor units

Question 76

Vancomycin ADRs

Answer 76

Vancomycin ADRs ## Footnote * Macular skin rash, chills, fever, rash * Red-man syndrome (histamine release): extreme flushing, tachycardia, hypotension * Ototoxicity, nephrotoxicity (33% with initial trough \> 20 mcg/mL)

Question 77

Fluoroquinolone Mechanism of Action

Answer 77

Fluoroquinolone Mechanism of Action ## Footnote Concentration-dependent, targets bacterial DNA gyrase & topoisomerase IV. Prevents relaxation of positive supercoils

Question 78

Fluoroquinolone ADRs

Answer 78

Fluoroquinolone ADRs ## Footnote * 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)

Question 79

Protein Synthesis Inhibitors Mechanisms of Action

Answer 79

Protein Synthesis Inhibitors Mechanisms of Action ## Footnote * 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

Question 81

Protein Synthesis Inhibitors ADRs

Answer 81

Protein Synthesis Inhibitors ADRs ## Footnote * 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