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Year 3 - Kinetics > 8 - Antimicrobials > Flashcards

8 - Antimicrobials Flashcards

1
Q

Pharmacokinetics is drug ______

A

Movement

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2
Q

Pharmacodynamics is drug _____

A

Activity

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3
Q

What is the triad of antimicrobials?

A
  • Infection
  • Pharmacokinetics
  • Pharmacodynamics
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4
Q

What determines infection?

A

Severity plus

  • Age
  • Co-morbidities
  • Immune function
  • Pathogen(s)
  • Site of infection
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5
Q

What determines pharmacokinetics?

A

Antimicrobial plus

  • Age
  • Body weight
  • Fluid status
  • Plasma proteins (albumin)
  • Organ function (dialysis)
  • Co-morbidities
  • Drug interactions
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6
Q

What determines pharmacodynamics?

A

Antmicrobial:

  • MOA
  • Potency (MIC)
  • Static or cidal activity
  • Resistance
  • Synergy/ antagonism
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7
Q

Define MIC

A

Lowest concentration of a specific agent needed to inhibit visible growth of an organism

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8
Q

Lower MIC = more _____ drug

A

Potent

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9
Q

Most common method of determining MIC

A

Disk diffusion (Kirby-Bauer method)

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10
Q

Limitations of MIC testing?

A
  • Lack of automation
  • Not studied in fastidious or slow-growing bacteria (ex: HACEK group)
  • Sometimes need quantitative instead of qualitative
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11
Q

What are MIC breakpoints?

A
  • Used to classify MICs into susceptible, intermediate, or resistant categories
  • Maximum MIC for the particular category (ex: anything at or below is reported as susceptible)
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12
Q

Define susceptible

A

Implies the infection should be effectively treated w/ the agent or recommended doses for the type of infection and infecting species, unless otherwise CI’d

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13
Q

Define intermediate

A
  • Indicates strains w/ MICs that may be at or above blood/tissue concs achieved w/ recommended doses
  • Response rates may be lower than for susceptible infections
  • Also implies potential clinical effectiveness if agent is physiologically concentrated at infection site or if higher doses can be used
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14
Q

Define resistant

A

Indicates stains w/ MICs that may not be inhibited by systemic concs usually achieved w/ recommended doses, and/or may fall w/in ranges where specific resistance mechanisms are likely (ex: beta-lactamases) or indicates that clinical studies have not demonstrated reliable efficacy

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15
Q

Why may MIC breakpoints differ for antimicrobials against the same organism?

A
  • MIC dependent on kinetics profile (protein-binding, free fraction)
  • Drugs w/ higher systemic availability will have higher breakpoints
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16
Q

Why may MIC breakpoints differ for infection site for the same antimicrobial against the same organism?

A
  • MIC based on drug’s ability to get to the infection site

- Ex: meningitis MIC for penicillin will be lower than for bloodstream b/c not as much penicillin can get in CSF

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17
Q

Why do some MIC breakpoints differ for antimicrobial route of administration?

A

Bioavailability

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18
Q

What are the goals of using PK-PD based antimicrobial dosing in px?

A
  • Increase likelihood of success

- Minimize emergence of resistance

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19
Q

What is mutant selection window (MSW)?

A
  • Range of antibiotic concentration in which drug-resistant bacteria mutants can be selectively enriched and amplified
  • Concentration zone is between MIC of susceptible pathogens and that of the least susceptible mutants (MIC -> MPC)
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20
Q

What is mutant prevention concentration (MPC)?

A

Antibiotic concentration that corresponds to MIC of the least susceptible mutants in a colony

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21
Q

What are the limitations in using MPC and MSW to dose patients?

A
  • Doses needed to achieve MPC are higher than those for curing and exceed those registered for the drug
  • Sometimes MPC is unattainable
  • Increased risk of adverse effect
  • MSW hasn’t been studied in many infective pathologies or at the site of infection
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22
Q

Which antimicrobials are concentration dependent?

A
  • Aminoglycosides

- [Fluoroquinolones]

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23
Q

Which antimicrobials are time dependent?

A
  • Penicillin
  • Cephalosporins
  • Carbapenems
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24
Q

Which antimicrobials are both concentration and time dependent?

A
  • FQs
  • Vancomycin
  • Linezolid
  • Daptomycin
  • [AGs, macrolides, tetracyclines]
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25
Q

Do px w/ cystic fibrosis have very high or very low drug clearance? Why is this?

A
  • Very high; can be 50% higher than px w/o CF

- Don’t exactly know why; may be due to total body water and how drugs are handled in the lungs

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26
Q

Which px are most likely to benefit from individualized antimicrobial dosing?

A
  • Serious infections w/ high rates of complications, tx failure, or mortality
  • Infections associated w/ relatively resistant pathogens
  • Px who are immunocompromised due to malignancy, neutropenia, diabetes, renal disease, HIV/AIDS, critical illness, immunosuppressant therapy
  • Pt populations w/ altered or variable PK due to age, obesity, organ dysfunction, dialysis, critical illness
  • Px who are predisposed to dose-related adverse effects or toxicity
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27
Q

Do we adjust doses for a critically ill px w/ a low serum creatinine due to hyper glomerular filtration?

A

No

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28
Q

Gentamicin is more active against _____, while tobramycin is more active against _____

A
  • E. coli

- Pseudomonas

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29
Q

PD target for aminoglycosides

A
  • fCmax/MIC > 8-10x**

- AUC24 / MIC (> 80)

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30
Q

Dettli equation

A

ke = 0.0024 * Clcr + 0.01

31
Q

What is Dettli equation used for?

A

Aminoglycosides ONLY

32
Q

PD target for vancomycin

A

AUC/MIC > 400 & < 700

33
Q

What is the importance of trough serum concentrations for vancomycin?

A
  • Used as a surrogate for AUC
  • Assuming that troughs of 15-20 will correlate to AUC/MIC 400-700
  • New guidelines will say to measure AUC b/c doses are being changed based on troughs when AUC is within the range
34
Q

How was Clcr calculated in the Wesner nomogram for vancomycin?

A

Using IBW / DW

35
Q

How was Clcr calculated in the Thalakada nomogram for vancomycin?

A

Wasn’t calculated; only use sCr and age

36
Q

How was Clcr calculated in the Kullar nomogram for vancomycin?

A

ABW

37
Q

How do you calculate %T>MIC?

A

(ln Cmax - ln MIC) / ke

- Written as a % of the dosing interval, where in most cases t’ can be included in the time above MIC

38
Q

PD target for beta-lactams

A

%fT>MIC
> 40% (static)
> 70% (cidal)
> 75-100% (serious infection)

39
Q

PD target for fluoroquinolones

A

f AUC/MIC > 90 (gram neg and pseudomonas)

> 30 (Strep pneumoniae)

40
Q

What is the adjustment factor (AF) for antimicrobials?

A
  • 30% for beta-lactams, daptomycin, and linezolid

- 40% for AGs, FQs, and vanco

41
Q

How do you calculate DW?

A

IBW + AF (ABW-IBW)

42
Q

What is ideal body weight?

A
  • Males = 50 kg + 2.3 kg for every inch above 5 feet

- Females = 45.5 kg + 2.3 kg for every inch above 5 feet

43
Q

Aminoglycosides are used w/ beta-lactams for synergy in tx of _____ infections

A

Streptococcal and enterococcal

44
Q

Vd of AGs

A

0.2-0.3 L/kg

45
Q

AG protein binding

A

< 10%

46
Q

AG t1/2 in normal renal function

A

2-3 h

47
Q

Desired peak and trough levels for AGs (normal dosing)

A
  • Peaks 6-10 mg/L; 8-10 mg for LRTIs and other serious infections; 4-6 mg/L for uncomplicated TI
  • Troughs 0.5-1.5 mg/L
48
Q

Loading dose for AGs (normal dosing)

A

2 mg/kg based on ABW or DW in obesity > 130% of IBW (round to nearest 10 mg)

49
Q

Maintenance dose for AGs (normal dosing)

A
  • Use nomogram

- % of loading dose based on Clcr

50
Q

How often should AG peaks and troughs be measured?

A
  • Around the 3rd dose
  • Repeat every 3-4 days
  • Draw troughs prior to dose, and peaks 30 mins after end of infusion
51
Q

Desired peak and trough levels for AGs used for synergy (normal dosing)

A
  • Peak 3-5 mg/L

- Trough 0.5-1 mg/L

52
Q

How should you monitor AGs for nephrotoxicity?

A
  • Follow sCr, blood urea nitrogen, and urine output 2-3 times/week
53
Q

Risk factors for nephrotoxicity w/ AGs

A
  • High trough concs
  • Duration of therapy
  • Advanced age
  • Diabetes
  • Dehydration
  • Concurrent nephrotoxins
54
Q

How should you monitor AGs for ototoxicity?

A
  • Assess for signs of vertigo, tinnitus, double-vision, pressure/ fullness/ pain in ears and new onset hearing loss especially if duration > 5 days
  • Doesn’t correlate w/ peak or trough levels
55
Q

Risk factors for auditory and vestibular toxicity w/ AGs

A
  • Auditory = age, genetic predisposition, and pre-existing hearing deficit
  • Vestibular = duration of therapy and cumulative exposure
56
Q

Benefits of extended-interval AG dosing

A
  • May provide better PD target attainment against pathogens w/ elevated MICs (ex: pseudomonas)
  • Higher concs may limit emergence of adaptive-resistance mechanisms
  • May reduce or delay nephrotoxicity
57
Q

When is extended-interval AG dosing not recommended?

A
  • CNS infections
  • Osteomyelitis
  • Enterococcal endocarditis
  • Significant renal dysfunction (Clcr < 40 mL/min)
58
Q

Maintenance dose for AGs (EID)

A

5-7 mg/kg based on ABW or DW in obesity > 130% of IBW (round to nearest 10 mg)

59
Q

How often are AGs administered w/ EID?

A
  • q24h

- q36-48h in those w/ Clcr of 40-60 mL/min as long as accompanied by diligent monitoring

60
Q

When should peak and troughs levels be measured w/ EID?

A

Around 2nd dose and repeat every 3-4 days

61
Q

Target peak and trough for AG (EID)

A
  • Peak 16-24 mg/L

- Trough < 1 mg/L

62
Q

What should be done if troughs are 1-2 mg/L or > 2 mg/L w/ EID?

A
  • 1-2 mg/L reduce dose, extend interval, or change to traditional dosing
  • > 2 mg/L change to traditional dosing
63
Q

What is VISA?

A

Vancomycin-intermediate susceptible staph aureus)

64
Q

Vd and protein binding of vancomycin

A
  • Vd = 0.7 L/kg (0.9 L/kg for critically ill)

- Protein binding = 50% (estimate)

65
Q

t1/2 of vancomycin in normal renal function

A

6-8 h

66
Q

Loading dose for vancomycin

A

25-30 mg/kg based on ABW or DW (round to nearest 250 mg increment)

67
Q

Maintenance dose for vancomycin

A

10-20 mg/kg (round to nearest 250 mg increment) every 8-12 h

68
Q

Matzke regression correlation

A

ke = 0.00083 * Clcr + 0.0044

69
Q

When is Matzke regression correlation used?

A

Vancomycin

70
Q

When should vanco peaks and troughs be measured?

A
  • Around 3rd or 4th dose and repeated weekly

- Draw troughs prior to dose, and collect peaks 1-2 h after infusion

71
Q

Target peak and trough for vancomycin

A
  • Peak < 40 mg/L
  • Trough 10-20 mg/L (15-20 mg/L for complicated infections like bacteremia, endocarditis, osteomyelitis, meningitis, hospital-acquired pneumonia)
72
Q

What does Red man syndrome look like?

A

Rash/erythema of face, neck, and upper torso (sometimes hypotension)

73
Q

What are the suggested infusion times for vanco?

A
  • 1 h for 1 g or less
  • 1.5 h for 1.25-1.75 g
  • 2 h for 2 g or more
74
Q

What is a normal BUN (blood urea nitrogen)?

A

2.5 - 7.1 mmol/L

Year 3 - Kinetics (12 decks)

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