Chapter 175 - Antimicrobial use in the critical care patient

Question 1

What are the factors that increase the risk of infection with a multidrug- resistant microbe?

Answer 1

• Previous antimicrobial exposure (within the last 3 months)
• Invasive procedures
• Longer duration of hospital stay (>5 days)
• Inappropriate dosing regimens
• Environment (community, hospital)
• Immunosuppressive disease or therapy
• Bacterial translocation from the GI tract
• Placement of foreign materials with surfaces conductive to bacterial colonization (i.e. indwelling catheters)

Question 2

What is the most common gram-negative commensal GI microbe?

Answer 2

E. coli

Question 3

What is the most common gram-positive commensal GI microbe?

Answer 3

Enterococcus spp

Question 4

How do organisms share genes imparting resistance?

Answer 4

Via integrins, plasmids, and transposons

Question 5

What is the colony-forming units (CFU) limit after which we should anticipate resistance to any antimicrobial drug?

Answer 5

> 10^6 - 10^8 CFU whether the population is a commensal resident or an infecting pathogen

Question 6

Give examples of problematic antibiotic-resistant pathogens

Answer 6

• Methicillin-resistant Staphylococcus aureus (MRSA)
• Vancomycin-resistant S. aureus (VRSA)
• Vancomycin-resistant Enterococcus
  (VRE)
• Fluoroquinolone-resistant Pseudomonas (FQRP) and E. coli,
• Fluoroquinolone-resistant Clostridium difficile

Question 7

Define multidrug resistance

Answer 7

Resistance to three or more antimicrobial

drugs to which the organism is generally considered susceptible

Question 8

In a teaching hospital, what were the doses of amoxicillin and enrofloxacin associated with expression of resistance to the treatment by fecal E. coli within 3 to 5 days of therapy?

Answer 8

• Amoxicillin 10 mg/kg q12

- Enrofloxacin 5 mg/kg q24

Question 9

Define nosocomial infection

Answer 9

Infection arising more than 48 hours after hospital admission

Question 10

What are the 4 primary drivers that reduce the advent of antimicrobial resistance in health care environments (Centers for Disease Control and Prevention recommendations)?

Answer 10

(1) timely and appropriate initiation of antibiotics;
(2) appropriate administration and deescalation of antibiotics;
(3) data monitoring, transparency, and stewardship infrastructure;
(4) availability of expertise at the point of care.

Question 11

T/F: Use of restrictive formularies to didacte the use of antibiotics are effective to reduce antimicrobial resistance

Answer 11

F

Question 12

In human patients with septic shock, what is the survival rate’s decline for each hour’s delay in the administration of appropriate antimicrobial therapy after the onset of hypotension?

Answer 12

7.6%

Question 13

T/F: The use of broad-spectrum antibiotics decreases the risk of resistance

Answer 13

F

Question 14

What is the reported rate of incorrect empiric choices in treating patients in shock in humans?

Answer 14

About 50%

Question 15

Which bacteria are more likely to be associated with:

• Genitourinary tract
• Abdominal infection
• Granulocytopenic or otherwise immunocompromised patients
• Deep isolated areas

Answer 15

• Genitourinary tract: gram-negative aerobes
• Abdominal infection: gram-negative aerobes, anaerobes
• Granulocytopenic or otherwise
  immunocompromised patients: gram-negative aerobes
• Deep isolated areas: anaerobes

Question 16

T/F: Rational combination antimicrobial therapy can be a powerful tool for enhancing effectiveness while reducing resistance in the CCP.

Answer 16

T

Question 17

What is the population size (CFU) of bacteria necessary for spontaneous mutations to happen and cause resistance to 2 drugs?

Answer 17

> 10^14 CFU

Question 18

Why should we avoid to use bacteriostatic drugs in association with Beta-lactams?

Answer 18

Beta-lactams’ bactericidal activity depends on continued synthesis of bacterial proteins –> bacteriostatic drugs inhibit microbial growth = antagonistic effects

Question 19

How do Beta-lactams and aminoglycosides act synergistically?

Answer 19

Beta-lactams induce cell wall failure and facilitate the penetration of aminoglycosides into the cell

Question 20

T/F: In humans, broadening the antimicrobial spectrum by combining at least two antimicrobials is recommended in patients with pneumonia

Answer 20

T

Question 21

What are the three major considerations that should influence our antibiotics dosing regimen?

Answer 21

• The MIC of the infecting microbe
• Its relationship to plasma and tissue drug
  concentrations achieved at the site of infection
• The impact of microbial and host factors that impact active drug concentrations achieved at the site of infection

Question 22

What is MIC useful for? (2)

Answer 22

MIC data, is critical both to identify current bacterial resistance in patients at risk and to design an individual patient dosing regimen

Question 23

What is the meaning of a MIC that is very close to the susceptible breakpoint?

Answer 23

Some level of resistance has already begun to emerge in isolates classified as susceptible.

Question 24

What best define the efficacy of time-dependent antibiotics?

Answer 24

The time during which the plasma drug concentration is above the MIC

Question 25

What are the mechanisms of action that make antibiotics time-dependent drugs?

Answer 25

- Cell wall inhibitors - Folic acid inhibitors - Drugs considered to be bacteriostatic.

Question 26

What is the recommended time during which the plasma drug concentration should be above the MIC for carbapenems?

Answer 26

25%

Question 27

Give 2 families of concentration-dependent antibiotics

Answer 27

Fluoroquinolones, aminoglycosides

Question 28

What is the recommended Cmax: MIC for concentration-dependent antibiotics? (Cmax target maximum concentration)

Answer 28

> 10-12

Question 29

What are the three levels of drug penetration (capillaries types and distribution) in normal tissues?

Answer 29

- Sinusoidal capillaries (adrenal cortex, pituitary gland, liver, spleen) -> No barrier to bound or unbound drugs - Fenestrated capillaries (kidneys, endocrine glands) -> No barrier to unbound drugs - Continuous capillaries (brain, CSF, testes, prostate, muscle, adipose tissue) -> Barrier that preclude drug movement

Question 30

Why should we interpret MIC with caution for highly protein bound antibiotics if the infection affects the kidneys, brain, CSF, testes, prostate, muscle or adipose tissue?

Answer 30

MIC is determined in vitro in the absence of protein. The MIC may underestimate the total plasma concentration of unbound drug necessary for effectiveness (only form that can penetrate these organs through fenestrated and continuous capillaries)

Question 31

In tissues with fenestrated and continuous capillaries, is it more recommended to favor water-soluble or lipid-soluble antibiotics?

Answer 31

Lipid-soluble drugs. Since these capillaries are not permeable to protein-bound drugs, lipid-soluble drugs are recommended to cross the phospholipid barrier and reach MIC more easily in these tissues

Question 32

Based on a human study, what is the percentage of β-lactams or aminoglycosides in plasma that reaches bronchial secretions?

Answer 32

2 - 30% (water-soluble)

Question 33

Give one family of antibiotics that can accumulate in tissue and exceed the plasma concentration (useful in the presence of marked inflammatory debris).

Answer 33

Macrolides (i.e azithromycin concentration in bronchial secretions is 17-fold higher than plasma concentrations)

Question 34

Give two reasons for which a drug, even if excreted in the urine, may not be effective to treat a UTI

Answer 34

- Drugs excreted in the urine may not concentrate there in the face of altered renal function - The drug may not be able to penetrate uroepithelial cells or biofilm protecting the organisms causing cystitis

Question 35

What factors can influence the distribution of a drug?

Answer 35

- Tissue perfusion (i.e. shock) - Lipophilicity (lipophilic drugs have a larger volume of distribution) - Accumulation of fluid in peripheral tissues (i.e. interstitial edema, pleural and peritoneal effusion) which will increase the volume of distribution of the water-soluble drugs - Aggressive fluid therapy - Hypoalbuminemia (for protein-bound drugs but also because of peripheral fluid retention)

Question 36

Ideally, how should we monitor the antibiotics plasma concentration in critical patients with variable absorption, volume of distribution and elimination?

Answer 36

Peak serum sample collected 1 to 2 hours after administration and a second sample obtained 4 to 6 hours --> So that both peak concentration (important for efficacy) and trough concentration (important for safety) can be predicted.

Question 37

In case of hypoalbuminemia, how should the dosage of antibiotics be adapted?

Answer 37

1.5 to 2-fold increase due to the increased volume of distribution

Question 38

What are the factors that influence elimination half-life? (2)

Answer 38

``` Distribution Clearance (depends on metabolism, drug interaction, GFR, renal function, lipophilicity) ```

Question 39

In general, is clearance decreased or increased in septic shock?

Answer 39

Increased due to the hyperdynamic state. | For any other critical illness, clearance is generally decreased.

Question 40

Give one family of antibiotics whose mechanism depends on oxygen tension

Answer 40

Aminoglycosides require aerobic active transport into the microbes

Question 41

What are the water-soluble antibiotics families?

Answer 41

Aminoglycosides, β-lactams and | glycopeptides

Question 42

What is the ''inoculum effect''?

Answer 42

This is the association between a large inoculum and the risk of therapeutic failure: - Larger inocula present more bacterial targets and thus require more drug molecules (higher doses). - Larger inocula present a greater risk of spontaneous mutations resulting in resistance - Larger inocula produce greater concentrations of destructive enzymes.

Question 43

Define biofilm

Answer 43

A biofilm is a community that effectively allows a single-cell microbe to become a multicell organism. It consists of microcolonies of both pathogenic and host microbes embedded in a polysaccharide produced by microbes adhering to surfaces. These include foreign bodies, wound surfaces, or other tissues

Question 44

T/F: The biofilm formed on indwelling catheter is a good representation of the organisms infecting the tissues

Answer 44

F

Question 45

What is the most common toxicity associated with: Aminoglycosides Fluoroquinolones

Answer 45

- Aminoglycosides: nephrotoxicity - Fluoroquinolones: retinal degeneration in cats / streptococcal toxic shock and necrotizing fasciitis in animals with Streptococcus canis

Question 46

When should we see clinical and microbiologic improvement after initiation of effective antibiotics?

Answer 46

Within the first 48-72 hours