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Plasmids. Chromosome. Antimicrobials 4: Testing and Selection. Dr Fiona Walsh. Role of Antibiotic Therapy. Prevention or Cure Cure or control Benefits outweigh disadvantages Efficient treatment Test bacteria sensitivity Understand antibiotic in human body . Objectives of lecture.

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slide1

Plasmids

Chromosome

role of antibiotic therapy
Role of Antibiotic Therapy
  • Prevention or Cure
  • Cure or control
  • Benefits outweigh disadvantages
  • Efficient treatment
    • Test bacteria sensitivity
    • Understand antibiotic in human body
objectives of lecture
Objectives of lecture
  • Sensitivity/Resistance testing methods
  • Pharmacokinetics
    • Science of time course of drug in body
    • Increase effectiveness/reduce toxicity
  • Pharmacodynamics
    • Relationship between drug concentration at site of infection and pharmacological response
sensitivity tests
Sensitivity tests
  • Susceptible or resistant to antibiotic
  • MIC = Minimum inhibitory concentration
  • MBC = Minimum bactericidal concentration
  • Minimum concentration required to inhibit growth
    • Disc diffusion
    • Agar dilution
    • Etest
    • Breakpoint MIC
slide6

Disc

Concentration

Gradient

Diffusion of antibiotic from a paper disc

After

Incubation

Area of

Bacterial

growth

Disc

Concentration of

Zone of

antibiotic at

Sensitivity

periphery of zone

equals the MIC

minimum inhibitory concentration mic determination

2

0

1

4

8

16

Minimum Inhibitory Concentration (MIC) Determination

Breakpoint

10

8

6

Number

4

2

0

1

2

4

8

16

>16

Minimum Inhibitory Concentration (mg/L)

(mg/L)

slide8
MIC
  • Breakpoint: concentration above which the isolate is described at resistant and below which is susceptible

e.g. S < 8mg/L R ≥ 8mg/L

Breakpoint = 8mg/L

  • Range: Lowest to highest MIC for population
  • MIC50 Median for series of MICs
  • MIC90
    • MICs of population ordered from lowest to highest
    • MIC value of the strains that appears 90% up the series.
    • Antibiotic considered to be successful if > 90% of population inhibited.
    • Also show if resistance is emerging i.e. 10% of population resistant.
evaluation of laboratory tests
Evaluation of Laboratory Tests
  • MIC test on plates is the best
    • Time consuming and costly
    • Most detailed
  • Disc test/Etest is easiest
    • Requires more skill to interpret
  • Breakpoint
    • Least skill required
    • Technique must be exact
    • Can be read by computer
    • Large amounts of data
minimum bactericidal concentration

MIC

64

32

16

16

8

8

4

4

2

2

1

1

mg/l

mg/l

Minimum Bactericidal Concentration

Subculture onto drug-free agar

MBC

pharmacokinetics pharmacodynamics
Pharmacokinetics/Pharmacodynamics
  • General terms for any drug, not antibiotic specific
  • The term pharmacokinetics is used to define the time course of drug absorption, distribution, metabolism and excretion.
  • The term pharmacodynamics refers to the relationship between drug concentration at the site of action and pharmacologic response.
    • However, when we apply these principles to antimicrobial therapy there are a number of factors that can alter the predicted outcome of therapy.
phamacokinetic definitions
Phamacokinetic Definitions
  • Clearance is the removal of the drug from plasma and relates the rate at which a drug is given and eliminated to the resultant plasma levels (volume/time)
  • Cmax is the maximum concentration reached at the site of infection, usually taken as the peak serum level.
  • tmax is the time taken, after dosage, to reach the Cmax.
  • Half-life (t½) is the time taken for the concentration of the drug in the plasma to decrease by half. This is often used as an indicator as to how often the drug should be administered.
phamacokinetic definitions17
Phamacokinetic Definitions
  • Area Under the Curve (AUC) is the parameter that links clearance to dosing. It is easily calculated: Initial concentration / Elimination rate constant.
  • Area Under the Inhibitory Curve (AUIC) is an antimicrobial adaptation of AUC, it refers to the concentration of the drug which is able to exert antibacterial activity over a given organism for a specific time. The AUIC is the drug concentration (AUC) divided by the MIC90 for a specific bacterial species.
pharmacokinetics

Dosing interval

Dosing interval

tmax

Cmax

Pharmacokinetics

64

32

16

Concentration (mg/L)

8

4

2

1

Time (hours)

pharmacokinetics area under the curve

Area under the curve

MIC90

PharmacokineticsArea Under the Curve

30

20

Concentration (mg/L)

10

Time (hours)

AUC = Initial concentration / Elimination rate constant

AUIC = AUC ( drug concentration) / MIC90

AUIC Preferably  250 but usable if > 125

half lives

Half-lives

The half-life of the early antibiotics were quite short, perhaps only one hour or so. Therefore the antibiotic had to be administered many times per day.

With oral versions, this causes problems with patient compliance and with parenteral versions, this becomes expensive in resources.

Increasingly, the newer antibiotics have much longer half-lives, some up to 33 hours.

This means that the patient needs to be dosed just once a day in order to maintain sufficient drug concentrations.

toxicity the need to monitor serum levels

Dosing interval

64

32

16

8

4

2

1

ToxicityThe Need to Monitor Serum Levels

Initial dose

Concentration (mg/L)

0

5

10

15

20

25

30

Time (hours)

antibiotic assays

Initial dose

Dosing interval

64

Peak

32

16

8

4

Trough

2

1

Antibiotic Assays

Concentration (mg/L)

Time (hours)

post antibiotic effect pae

Antibiotic Induced death

1.6 hours to increase 1 log10

Removal of Antibiotic

1 log10 increase

3.1 hours to increase 1 log10

Control

Post-Antibiotic Effect (PAE)

Viable Count (cfu/ml)

PAE = 3.1 - 1.6 = 1.5 hours

Due to antibiotic effect only

quantification of post antibiotic effect pae
Quantification of Post-Antibiotic Effect (PAE)

The standard equation for PAE is:

PAE (hours) = T - C

T = is the time required for the count of cfu to increase 1 log10 (10-fold) above the count immediately seen after drug treatment

C = is the time required for the count to increase 1 log10 in an untreated control culture

PAE measures the time to reach normal logarithmic growth

post antibiotic effect

Post-Antibiotic Effect

Precise mechanism is still not understood

Examples of PAE

summary
Summary
  • Sensitivity testing
    • Advantages
    • Disadvantages
  • Pharmacological action of antibiotics
    • Ideal drug
    • Influence of factors on performance
  • Drug choice
    • Cheap
    • Most Effective
    • Least toxic