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Respiratory II > Drugs for Respiratory Infections > Flashcards

Drugs for Respiratory Infections Flashcards

1
Q

Drug Families

A

Aminopenicillins

B-lactamase Inhibitors

Third Generation Cephalosporin

Fourth Generation Cephalosporin

Glycopeptides

Aminoglycosides

Tetracyclines

Macrolides

Lincosamides

Oxazolidinones

Antivirals Antifungals

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2
Q

•Aminopenicillins

A

•Aminopenicillins

▫Ampicillin (PO, IV, IM)

▫Amoxicillin (PO)

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3
Q

•B-lactamase Inhibitors

A

•B-lactamase Inhibitors

▫Ampicillin-sulbactam [Unasyn] (IV)

▫Amoxicillin-clavulanic acid [Augmentin] (PO)

▫Piperacillin-tazobactam [Zosyn] (IV)

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4
Q

•Third Generation Cephalosporin

A

•Third Generation Cephalosporin

▫Ceftriaxone [Rocephin] (IV, IM)

▫Ceftazidime [Fortaz] (IV, IM)

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5
Q

•Fourth Generation Cephalosporin

A

•Fourth Generation Cephalosporin

▫Cefepime (IV, IM)

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6
Q

•Carbapenems

A

•Carbapenems

▫Meropenem [Merrem] (IV)

▫Ertapenem [Invanz] (IV, IM)

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7
Q

•Glycopeptides

A

•Glycopeptides

▫Vancomycin (PO, IV)

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8
Q

•Fluoroquinolones

A

•Fluoroquinolones

▫Levofloxacin [Levaquin] (PO, IV, topical)

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9
Q

•Aminoglycosides

A

•Aminoglycosides

▫Gentamicin (IV, IM, topical)

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10
Q

•Tetracyclines

A

•Tetracyclines

▫Doxycycline (PO, IV)

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11
Q

•Macrolides

A

•Macrolides

▫Azithromycin [Zithromax, Z-pak] (PO, IV, topical)

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12
Q

•Lincosamides

A

•Lincosamides

▫Clindamycin [Cleocin] (PO, IV, IM, topical)

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13
Q

•Oxazolidinones

A

•Oxazolidinones

▫Linezolid [Zyvox] (PO, IV)

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14
Q

•Antivirals

A

•Antivirals

▫Oseltamivir [Tamiflu] (PO)

▫Zanamivir [Relenza] (INH)

▫Amantadine (PO)

▫Rimantadine (PO)

▫Acyclovir (PO, IV, topical)

▫Valacyclovir [Valtrex] (PO)

▫Ganciclovir [Cytovene] (PO, IV)

▫Valganciclovir [Valcyte] (PO)

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15
Q

•Antifungals

A

•Antifungals

▫Fluconazole [Diflucan] (PO, IV)

▫Itraconazole (PO)

▫Voriconazole [Vfend] (PO, IV)

▫Amphotericin B (IV)

▫Caspofungin (IV)

▫Micafungin (IV)

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16
Q

Site of Antibacterial Action

A
  • Cell wall synthesis
  • Cell membrane synthesis
  • Protein synthesis
  • Nucleic acid metabolism
  • Function of topoisomerases
  • Folate synthesis
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17
Q

β-Lactam
Mechanism of Action

A

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

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18
Q

β-Lactam
ADRs

A

•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
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19
Q

Vancomycin
Mechanism of Action

A

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

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20
Q

Vancomycin
ADRs

A
  • Macular skin rash, chills, fever, rash
  • Red-man syndrome (histamine release): extreme flushing, tachycardia, hypotension
  • Ototoxicity, nephrotoxicity (33% with initial trough > 20 mcg/mL)
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21
Q

Fluoroquinolone
Mechanism of Action

A

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

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22
Q

Fluoroquinolone
ADRs

A
  • 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)
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23
Q

Protein Synthesis Inhibitors
Mechanisms of Action

A

•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

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24
Q

Protein Synthesis Inhibitors
ADRs

A

•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
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25
Q

Community-Acquired Pneumonia (CAP)

A

•CAP + Influenza (2005)

▫8th leading cause of death in the U.S.

▫> 60,000 deaths due to pneumonia in U.S.

•Most severe manifestations in:

▫Very young, elderly, chronically ill

•Goal of CAP treatment: eradicate organism, resolve clinical disease

▫Antibiotics = mainstay of therapy

▫Therapy guided by organism and susceptibility

▫Must have knowledge of most likely infecting

pathogen and local susceptibility

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26
Q

CAP – Guidelines

A

•Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS)

▫Management of Community-Acquired Pneumonia

•Excluded patients:

▫Immunocompromised patients

▫Solid organ, bone marrow, or stem cell transplant

▫Those receiving chemotherapy

▫Long-term high dose corticosteroids (> 30 days)

▫Congenital or acquired immunodeficiency

▫HIV with CD4 count < 350 cells/mm3

▫Children ≤ 18 years

▫

▫

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27
Q

CAP – Initial Assessment

A

•Assessment of severity:

▫Outpatient, inpatient (non-ICU), ICU

•Avoid unnecessary admissions:

▫25x greater cost inpatient vs. outpatient

▫Resume normal activities faster as outpatient

▫Hospitalization carries risks: thromboembolic

events & superinfections

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28
Q

CAP – Severity of Illness Scores

A

•In conjunction: laboratory data, clinical evaluation, & physician interpretation

•CURB-65

▫Confusion

▫Uremia (BUN > 19 mg/dL)

▫Respiratory rate (≥ 30 breaths/min)

▫Low blood pressure

– SBP < 90 mmHg, DBP ≤ 60 mmHg

▫Age (≥ 65 Years)

•Pneumonia severity index (PSI)

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29
Q

CAP – CURB-65

A

Score 0-1: treat as an outpatient

Score 2: admit to hospital

Score ≥ 3: admit to ICU

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30
Q

CAP – Pneumonia Severity Index (PSI)

A
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31
Q

CAP – General Medical vs. ICU

A

•10% of hospitalized CAP patients require ICU stay

•Use CURB-65 + minor criteria to determine need for ICU admission:

▫Multilobar infiltrates

▫WBC < 4000 cells/mm3

▫PLT < 100,000 cells/mm3

▫Core temperature < 36 ˚C

▫Hypotension requiring aggressive fluid

resuscitation

•Two absolute indications for ICU admission:

▫Mechanical ventilation

▫Septic shock (+ vasopressors)

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32
Q

CAP – Diagnosis

A

•Clinical findings:

▫Cough, fever, sputum production, pleuritic chest

pain

•Demonstrable infiltrate on CXR required:

▫If negative but CAP suspected, initiate antibiotics

and repeat CXR in 24-48 hours

•Culture

▫Increased mortality & risk of treatment failure – if

inappropriate antimicrobials used

•Additional diagnostic testing

33
Q

CAP – Further Diagnostic Testing

A
34
Q

Organism Identification

Gram Pos

A

•Most valuable, time tested method for immediate ID of bacteria = gram stain

35
Q

Organism Identification

Gram Neg

A

•Most valuable, time tested method for immediate ID of bacteria = gram stain

36
Q

CAP – Common Infecting Organisms

A
37
Q

CAP – Infecting Organisms/Disease State

A

•Underlying bronchopulmonary disease:

▫H. influenzae

▫Moraxella catarrhalis

▫+ S. aureus during an influenza outbreak

•Chronic oral steroids or severe underlying bronchopulmonary disease, alcoholism, frequent antibiotic use:

▫Enterobacteriaceae

▫Pseudomonas aeruginosa

•Classic aspiration pleuropulmonary syndrome in alcohol/drug overdose or in seizures with gingival disease or esophageal motility disorders:

▫Anaerobes

38
Q

CAP – Other Infecting Organisms

A

•Common viruses:

▫Influenza

▫Respiratory syncytial virus (RSV)

▫Adenovirus

▫Parainfluenza virus

•Other viruses:

▫Human metapneumovirus

▫Herpes simplex virus (HSV)

▫Varicella-zoster virus (VSV)

▫SARS-associated coronavirus

39
Q

CAP – Other Infecting Organisms

2-3% incidence:

A

•2-3% incidence:

▫M. tuberculosis

▫Chlamydophila psittaci (psittacosis)

▫Coxiella burnetii (Q fever)

▫Francisella tularensis (tularemia)

▫Bordetella pertussis (whooping cough)

▫Endemic fungi

– Histoplasma capsulatum

– Coccidioides immitis

– Cryptococcus neoformans

– Blastomyces hominis

40
Q

CAP – Resistant Organisms

A

•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

41
Q

CAP – Empiric Antimicrobial Guidelines

•Outpatient Recommendations

A

•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

42
Q

CAP – Empiric Antimicrobial Guidelines

Inpatient, Non-Intensive Care Unit Recommendations

A

•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)

43
Q

CAP – Empiric Antimicrobial Guidelines

Inpatient, Intensive-Care Unit Recommendations

A

•Inpatient, Intensive-Care Unit Recommendations

– B-lactam IV (ceftriaxone, cefotaxime, or

ampicillin/sulbactam preferred) PLUS

azithromycin IV

-OR-

B-lactam IV (ceftriaxone, cefotaxime, or

ampicillin/sulbactam preferred) PLUS a

respiratory FQ (levofloxacin, moxifloxacin

44
Q

CAP – Modifying Empiric Regimen

A

•Pseudomonas aeruginosa risks:

▫Structural lung disease (bronchiectasis)

▫Repeated COPD exacerbations

– Frequent corticosteroid and/or antibiotic use

▫Prior antibiotic therapy

•Treatment:

–Antipseudomonal B-lactam IV (piperacillin-tazobactam, cefepime, imipenem, meropenem) PLUS either ciprofloxacin or levofloxacin

-OR-

–Antipseudomonal B-lactam PLUS aminoglycoside (gentamicin) AND azithromycin

-OR-

–Antipseudomonal B-lactam PLUS aminoglycoside AND antipneumococcal FQ

45
Q

CAP – Modifying Empiric Regimen

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) risks:

A

•Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) risks:

▫End-stage renal disease (dialysis)

▫Injection drug abuse

▫Prior influenza

▫Prior antibiotic use (especially FQ)

•Treatment:

▫Add vancomycin IV or linezolid

▫Panton-Valentine leucocidin necrotizing

pneumonia: add clindamycin or use linezolid

46
Q

CAP – Intravenous à Oral Therapy

A

•Transition to oral therapy:

▫Hemodynamically stable

▫Improving clinically:

– 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

▫Tolerating oral medications

▫Normal functioning GI

47
Q

CAP – Duration of Therapy

A

•Minimum of 5 days treatment

▫Most patients receive 7-10 days

•Must be afebrile for 48-72 hours

•No more than 1 CAP-associated sign of clinical instability

•Exception:

▫Pseudomonas – 8 day course led to more relapse

compared to 15 day course

48
Q

HCAP, HAP & VAP

A
  • HCAP: history of hospitalization or exposure to healthcare settings
  • HAP: occurs 48 hours or more after admission

▫2nd most common nosocomial infection in the U.S.

▫Increases hospital length of stay ~7-9 days

▫Incidence: 5-10 cases per 1000 admissions

•VAP: arises 48-72 hours after endotracheal intubation

▫Occurs in 9-27% of all intubated patients

▫Incidence increases with longer ventilation duration

49
Q

HCAP, HAP & VAP

Early onset vs Late onset

A

•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.

50
Q

Multi-Drug Resistant (MDR) Pathogens

Pseudomonas aeruginosa

A

•Pseudomonas aeruginosa

▫Resistance caused by multiple efflux pumps

▫Decreased expression of outer membrane porin

channel

▫Increasing resistance to:

– Piperacillin

– Ceftazidime

– Cefepime

– Imipenem

– Meropenem

– Aminoglycosides

– Fluoroquinolones

51
Q

Multi-Drug Resistant (MDR) Pathogens

Klebsiella, Enterobacter, Serratia

A

•Klebsiella, Enterobacter, Serratia

▫Klebsiella intrinsically resistant to ampicillin and can

acquire resistance to cephalosporins and

aztreonam à ESBL production

▫Enterobacter high frequency resistance

development to cephalosporins during treatment

▫These bacteria may carry plasmid mediated AmpC-

type enzymes (ESBL) which are carbapenem

susceptible but CONCERNED about resistance

– May become resistant by loss of an

outer membrane porin

52
Q

Multi-Drug Resistant (MDR) Pathogens

MRSA

DRSP

A

•MRSA

▫> 50% of ICU infections caused by S. aureus are

methicillin-resistant

▫PBPs with reduced affinity for B-lactams

▫Concern for linezolid resistance but still rare

•DRSP

▫Altered PBP

▫ALL MDR strains in US currently susceptible to

vancomycin and linezolid

53
Q

HCAP, HAP, & VAP – Diagnosis

A

•Radiographic infiltrate that is new or progressive

•Clinical findings suggestive of infection:

▫Fever

▫Purulent sputum

▫Leukocytosis

▫Decline in oxygenation

54
Q

Empiric Therapy – Early Onset

A

•Potential pathogens:

▫S. pneumoniae

▫H. influenzae

▫MSSA

▫Sensitive gram-negative: E. coli, K. pneumoniae,

Enterobacter spp., Proteus spp., Serratia

marcescens

•Treatment:

▫Ceftriaxone OR

▫FQ (levofloxacin, moxifloxacin, ciprofloxacin) OR

▫Ampicillin/sulbactam OR

▫Ertapenem

55
Q

Empiric Therapy – Late Onset

A

•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

56
Q

Combination vs. Monotherapy

A

•Combination therapy recommended to ensure at least one agent is active against the often MDR pathogen

•Often cited reasons for combination therapy:

▫To prevent resistance

– Evidence not well documented

▫To add synergy for treatment of P. aeruginosa

– Only proven valuable in neutropenia or

bacteremia

•Use monotherapy when possible

57
Q

Duration of Therapy

A

•VAP – good clinical response after 6 days

▫Prolonged courses leads to MDR pathogen

colonization

•Shorten duration to as short as 7 days (traditional 14-21 days)

▫Unless P. aeruginosa (8 days led to relapse à

requires longer treatment course)

58
Q

Pneumonia: DOC if Organism Known

•Streptococcus pneumoniae

•Haemophilus influenzae

A

•Streptococcus pneumoniae

▫Non-resistant

– Penicillin G

– Amoxicillin

▫Resistant

– Chosen on basis of susceptibility:

– Cefotaxime, ceftriaxone, levofloxacin,

moxifloxacin, vancomycin, linezolid

•Haemophilus influenzae

▫Non-B-lactamase producing

– Amoxicillin

▫B-lactamase producing

– 2nd or 3rd generation cephalosporin,

amoxicillin/clavulanate

59
Q

Pneumonia: DOC if Organism Known

•Mycoplasma pneumoniae

•Chlamydophila pneumoniae

A

•Mycoplasma pneumoniae

▫Macrolide (azithromycin, clarithromycin),

tetracycline (doxycycline)

•Chlamydophila pneumoniae

▫Macrolide (azithromycin, clarithromycin),

tetracycline (doxycycline)

•Chlamydophila psittaci

▫Doxycycline

•Legionella spp.

▫Fluoroquinolone, azithromycin, doxycycline

60
Q

Pneumonia: DOC if Organism Known

•Enterobacteriaceae (Klebsiella, E. coli, Proteus)

•Pseudomonas aeruginosa

A

•Enterobacteriaceae (Klebsiella, E. coli, Proteus)

▫3rd or 4th generation cephalosporin, carbapenem

(if ESBL producer)

•Pseudomonas aeruginosa

▫Antipseudomonal B-lactam PLUS ciprofloxacin,

levofloxacin, or an aminoglycoside

•Anaerobe (aspiration): Bacteroides, Fusobacterium, Peptostreptococcus

▫B-lactam/B-lactamase inhibitor, clindamycin

61
Q

Pneumonia: DOC if Organism Known

•Staphylococcus aureus

•Influenza virus

A

•Staphylococcus aureus

▫Methicillin-sensitive

– Antistaphylococcal penicillin (nafcillin, oxacillin,

dicloxacillin)

▫Methicillin-resistant

– Vancomycin or linezolid

•Influenza virus

▫Oseltamivir, zanamivir

62
Q

Pneumonia: DOC if Organism Known

A

•Pneumocystis jiroveci (P. carinii pneumonia)

▫Trimethoprim/sulfamethoxazole

•Bordetella pertussis

▫Azithromycin, clarithromycin

•Coccidioides spp.

▫No treatment necessary if normal host

–Itraconazole, fluconazole

•

•Histoplasmosis and Blastomycosis

▫Itraconazole

63
Q

Influenza

A

•Each year, 5-20% of population infected

•In the U.S.:

▫36,000 deaths

▫> 200,000 hospitalizations

•Transmission:

▫Respiratory droplets (cough, sneeze, talk)

▫Contaminated surfaces

▫Incubation: 1-4 days (average 2 days)

▫Viral shedding: day after symptoms to 5-10 days

after illness onset

64
Q

Influenza

Symptoms (abrupt onset):

A

•Symptoms (abrupt onset):

▫Fever

▫Myalgia

▫Headache

▫Malaise

▫Non-productive cough

▫Sore throat

▫Rhinitis

•Symptoms resolve after 3-7 days (uncomplicated)

▫Cough/malaise can last > 2 weeks

65
Q

Neurominidase Inhibitors

A

•Oseltamivir (PO), zanamivir (INH)

•MOA: analogs of sialic acid, interferes with release of progeny influenza virus from infected host cell

•PK:

▫Oseltamivir – orally administered pro-drug,

activated by hepatic esterases, t1/2 6-10 hours,

glomerular filtration and tubular secretion (renally

adjust)

▫Zanamivir – 10-20% reaches lungs, remainder

deposits in oropharynx, t1/2 2.8 hours, 5-15%

absorbed and excreted in urine with minimal

metabolism

66
Q

Neurominidase Inhibitors

ADRs

A

•ADRs

▫Oseltamivir – nausea, vomiting, abdominal pain (5-

10%), headache, fever, diarrhea, neuropsychiatric

effects

– Approved for children ≥ 1 year

▫Zanamivir – cough, bronchospasm, decrease in

pulmonary function (reversible), nasal/throat

discomfort, not recommended in underlying airway

disease

– Approved for children ≥ 7 years

67
Q

Neurominidase Inhibitors

  • Resistance:
  • Therapeutic use:
A

•Resistance:

▫Point mutation in viral hemagglutinin (HA) or

neuraminidase (NA) surface proteins

– -97.4% seasonal H1N1 resistant to

oseltamivir 2008-2009

– -Still susceptible to other drugs

•Therapeutic use:

▫Influenza prophylaxis (household and institutional)

▫Influenza treatment

68
Q

M2 Channel Blockers

A

•Amantadine (PO), rimantadine (PO)

•MOA: block M2 proton ion channels of virus inhibiting uncoating of viral RNA within host cell

▫Active against influenza A only

•PK:

▫Amantadine – t1/2 12-18 hours, excreted unchanged

in the urine, (renally adjust)

▫Rimantadine – 4-10x more active in vitro, t1/2 24-36

hours, extensive hepatic metabolism (renal and

hepatic adjustment)

69
Q

M2 Channel Blockers

ADRs:

Resistance:

A

•ADRs:

▫GI (nausea, anorexia)

▫CNS (nervousness, insomnia, light-headedness)

▫Severe behavioral changes

▫Delirium

▫Agitation

▫Seizures

•Resistance: point mutations, marked resistance limiting use of these agents

70
Q

Other Antivirals – HSV & VSV

A

•Acyclovir (PO, IV, topical), valacyclovir (PO)

•MOA: three phosphorylation steps for activation, first step via virus specific thymidine kinase. Inhibits DNA synthesis:

▫Competition with deoxyGTP for DNA polymerase à

binds DNA template irreversible complex

▫Chain termination following incorporation into viral

DNA

71
Q

Other Antivirals – HSV & VSV

  • PK:
  • Therapeutic use:
  • ADRs:
A

•PK:

▫Acyclovir – bioavailability 15-20%, t1/2 2.3-3 hours,

20 hours in anuria, diffuses into most tissues and

body fluids (including CSF)

▫Valacyclovir – L-valyl ester of acyclovir, rapidly

hydrolyzed in liver, serum levels 3-5x greater than

PO acyclovir, bioavailability 54-70%, t1/2 2.5-3.3

hours

•Therapeutic use: genital herpes (treatment, prophylaxis, suppression), varicella, HSV encephalitis, neonatal HSV treatment

•ADRs: nausea, diarrhea, headache

72
Q

Other Antivirals – CMV

A

•Ganciclovir (PO, IV), valganciclovir (PO)

•MOA: acyclic guanosine analog, requires activation by triphosphorylation before inhibiting DNA polymerase. Termination of DNA elongation.

•PK:

▫Ganciclovir – t1/2 4 hours, intracellular t1/2 16-24

hours, clearance related to CrCl

▫Valganciclovir – L-valyl ester, bioavailability 60%

•Therapeutic use: CMV retinitis treatment, CMV prophylaxis

•ADRs: myelosuppression, nausea, diarrhea, fever, peripheral neuropathy

73
Q

Antifungals

A

•Common fungi of clinical interest:

▫Candida albicans

▫Histoplasma capsulatum

▫Cryptococcus neoformans

▫Coccidioides immitis

▫Aspergillus spp.

▫Blastomyces dermatitidis

74
Q

Azole Antifungals

A

•Ergosterol found in cell membrane of fungi (compared to cholesterol used in bacteria and human cells)

•MOA: inhibits fungal cytochrome P450, reducing production of ergosterol

▫Selective toxicity due to greater affinity for fungal

rather than human cytochrome P450 enzymes

75
Q

Azole Antifungals

Therapeutic Use

ADRs

A

•Therapeutic use: wide spectrum of activity against Candida spp, blastomycosis, coccidiodomycosis, histoplasmosis, and even Aspergillus (itraconazole, voriconazole)

•ADRs: minor GI upset, abnormalities in liver enzymes

•Drug interactions!!

76
Q

Azole Antifungals

Agents

A

•Fluconazole (Diflucan) PO, IV

▫PK: water soluble, good CSF penetration, high PO

bioavailability ~96%

•Itraconazole PO

▫PK: drug absorption increased by food and low

gastric pH

•Voriconazole (Vfend) PO, IV

▫PK: well absorbed, bioavailability > 90%

▫ADRs: visual changes, photosensitivity

77
Q

Amphotericin B

A
  • MOA: binds ergosterol, changes permeability of cell, forms pores in membrane
  • PK:

▫Insoluble in water, variety of lipid formulations

available, poorly absorbed PO, t1/2 15 days, only 2-

3% of blood level reaches CSF

•Therapeutic use: broadest spectrum of activity, useful in life-threatening infections but very toxic

•ADRs: infusion related (fever, chills, vomiting, headache), cumulative toxicity (renal damage)

78
Q

Echinocandins

A

•Caspofungin, micafungin, anidulafungin (IV)

•MOA: inhibits synthesis of B(1-3)-glucan, disrupts fungal cell wall, and causes cell death

•Therapeutic use: Candida and Aspergillus

•ADRs: minor GI, flushing

Respiratory II (14 decks)

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