1. Pharmacokinetic and pharmacodynamic principles
for antibiotic use in bovine respiratory disease
Lorenzo Fraile
CReSA Researcher (program INIA-IRTA)

2. • Introduction. Bovine Respiratory Disease (BRD).
• Mechanisms of action of antibiotics.
• Pharmacokinetics and Pharmacodynamics.
A brief overview.
• Treatment of pneumonia. General concepts.
• Posology regimen of antibiotics.
• Application of antibiotic therapy to the treatment
of BRD.
Presentation

3. Bovine Respiratory Disease
(BRD)

4. -Cough
-Dyspnoea
-Abdominal breathing
Symptoms Population level -Mortality
-Morbidity
-Growth retardation
-Increase feed conversion ratio
-Appearance of runts
Economic consequences

5. Host
Environment
BRD etiopathogeny
Genetic background
Productivity
Production system
Density
Microorganism

6. • Pasteurella multocida (1 P, 3 C).
• Mannheimia haemolytica (1 P, 3 C).
• Mycoplasma bovis (2 P, 3 C).
• Haemophilus somnus (1P, 2C).
• Bovine Herpesvirus type I (3P, 1C).
• Bovine respiratory syncytial virus (3P, 3C).
• Bovine coronavirus (1P, 1C).
• Paraninfluenza 3 virus (1P, 1C).
• Bovine viral diarrhoea virus (3P, 2C).
Infectious agents - BRD
Note:
P= Primary infectious agent; C= Secondary infectious agent
The higher the value, the most relevant is.

7. Mechanisms of action of
antibiotics

8. Mechanisms of action of
antibiotics

9. Pharmacokinetics and Pharmacodynamics.
A brief overview.

10. Host
Drug Microorganisms
(Bug)
Susceptibility
Pharmacodynamics
Infection
Im
m
unesystem
ToxicityPharmacokinetics
Do we really know how antibiotics are
applied?

11. • Pharmacokinetics (PK):
– AUC
– Tmax
– Cmax
– Clearance (mL/min/kg bw)
• Pharmacodynamics (PD)
– MIC (Minimal Inhibitory
Concentration)
– MBC (Minimal Bactericidal
Concentration)
PK and PD parameters
Pharmacokinetic: Where???
• Plasma
• Lung homogenate
• Bronchoalveolar lavage
• Pulmonary Epithelial Lining Fluid (PELF)

12. PK parameters

13. PD parameters
• Strain level
– MIC- Minimal inhibitory concentration. It is the lowest
antimicrobial concentration that is able to inhibit completely the
bacterial growth after 24-48 hours of incubation - It is determined in
vitro using a dilution method in Agar or culture media
(Document CLSI M31).
– MBC-Minimal bactericidal concentration. It is the lowest
antimicrobial concentration that is able to reduce the initial bacterial
population in three log units (3 log10 step) after 24-48 hours of
incubation - It is determined in vitro using a dilution method in Agar
or culture media (Document CLSI M26).
• Population level
– MIC50 and MIC90 (include the 50 o 90% of the isolated strains)

14. Pharmacodynamics parameters
Watts et al, J Clin Microbiol. 1994

15. Treatment of pneumonic disease

16. Where is the pathogen?
Pharmacokinetic: Where???
• Plasma
• Lung homogenate
• Bronchoalveolar lavage
• Pulmonary Epithelial Lining Fluid (PELF)

17. Ratio 1-2: Fluoroquinolones: The antibiotic is
located in the extracellular and intracellular
compartment.
Ratio 7-8: Macrolides (in general): The antibiotic
is concentrated in the intracellular compartment.
pasteurella
pasteurella
Where is the antibiotic?
Antimicrobial against Pasteurellaceae must be present
in the extracellular compartment
Study in detail the antibiotic concentration present in the compartments.
Perhaps pulmonary epithelial lining fluid is the best to know the “real situation”…

18. Posology regimen of antibiotics

19. • Time-dependent versus concentration
dependent– It depends on how it works to
destroy the bacteria.
• Where is the antibiotic? It must be
interpreted precisely where the antibiotic is
located.
Are all the antibiotics similar?

20. Fluoroquinolone and Mannhemia haemolytica
Concentration
dependent
Concentration-dependent antibiotics

21. Time-dependent antibiotic
An increase in concentration
It does not imply a quicker
decrease of the bacterial load
Cephalosporin of human use

22. Azithromycin (a human case)
Time-dependent antibiotic

23. Classical concept of antibiotic
treatment
It is true for macrolides (classical) and
Beta-lactam antibiotics
MIC
Clearance x MIC90
Bioavailability
Dose =

24. PK/PD parameters
Threshold values:
AUC0--24:MIC = 125
Cmax:MIC = 10
T (inter-dosing interval)>(1-5)* MIC= 40-100%

25. Are all the antibiotics similar?
• Bactericidal versus bacteriostatic
Only indicative. It must be studied each antimicrobial with each bacteria
Action Group Examples
Mainly bacteriostatic Phenicols
Macrolides
Lincosamides
Tetracyclines
Florfenicol
Tiamulin
Lincomycin
Doxycycline
Mainly bactericidal
time-dependent
Penicillin
Cephalosporins
Cefquinome
Ceftiofur
Amoxicillin
Mainly bactericidal
concentration-
dependent with
relevant post-antibiotic
action
Aminoglycosides
Fluoroquinolones
Marbofloxacin
Enrofloxacin
Amikacin
Streptomycin

26. Components Tools to investigate
Dose Dose determination studies
or PK/PD
Administration interval. PK/PD
Length of treatment. Clinical end-point
Place and site of administration Pharmacokinetics
Posology regimen of antibiotics

27. Dose determination studies
Dose Response
Black box
PK/PD
Dose
PK PD
Plasmatic
concentration
surrogate
Response

28. • Null hypothesis
– placebo = D1 = D2 = D3
• Lineal statistical model
– Yj = wj + j
• Conclusion
– D3 = D2 > D1 > Placebo
Placebo Dose
Response
1 2 3
*
*
NS
Selected dose
Dose determination studies
Bovine respiratory disease
• Experimental infectious model
• 5 animals per group
• 3 doses
• Critical end-points:
• Mortality
• Bacteriology
• Clinical symptoms

29. “Response”“Exposure”
• Concentration/time
profile
• AUC
• Cmax , Cmin
• “Biomarker” (Acute
phase proteins)
• Clinical end-point
PK/PD models

30. What about the end-point?
0
30
60
90
0 0.5 2 16 64
Dose (mg/kg)
Response%
Mortality
Bacterial excretion Ceftiofur
N = 383 cerdos

31. • Dose (mg/kg body weight/day)
– weight
• Administration frequency
– one only dose (one “shot”)
– one dose every 24, 48, x hours
• Treatment length
– 24 hours
– 1, 2, 3…. X days
• Way of administration
– oral
– parenteral
• intramuscular
• subcutaneous
Summary of posology regimen

32. Application of antibiotic therapy to
the treatment of BRD

33. • Antibiotic families
(most frequently
used)
– Tetracyclines
– Beta-lactam
antibiotics
– Macrolides
• Classical
• Ketolides
• Azalides ----
Gamithromycin
– Phenicols
– Fluoroquinolones
• Way of
administration
– Intramuscular
– Subcutaneous
– Oral (bioavailability)
• water
• milk
• feed
Available options (I)

34. • It is administered with the goal of:
– therapy
– metaphylaxia (risk population)
– prophylaxia
• Antibiotic combination:
– why?
– what about the goal?
– how?
• Individual versus population treatment
Available options (II)

36. • To be studied:
– age (pre-ruminant vs. ruminant)
– type of production/facilities
– breed
– gestation/lactation
– disease
– management/nutrition
Population pharmacokinetics

37. • Demographics
– age, weight, sex and breed
• Genetic
– CYP2D6, CYP2C19
• Environment
– diet
• Physiologic or patho-physiologic:
– renal (creatinin clearance) or hepatic damage
• Concomitant drugs (non-steroidal anti-inflammatory
drugs).
• Other factors: Circadian rhythm and formulations.
Factors that explain
inter-individual variability

38. Variability is a biological fact …

39. n = 215
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
-5 0 5 10 15 20 25 30
Time (h)
Concentrationsmg/mL
Doxycycline 20 mg/Kg body weight/day by drinking water
Interindividual pharmacokinetic variability

40. 0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
0 1 2 3 4 5 6
Sample time
Concentrations(µg/mL)
Interindividual pharmacokinetic variability
Amoxycillin 500 ppm by feed

41. • To know the variation of key pharmacokinetic
parameters inside a population.
– clearance (media and standard deviation)
– bioavailability
• To know the variation of key pharmacodynamic
parameters (MIC) inside a population.
• THE LOWER THE VARIATION, THE BETTER TO
GUARANTEE THE EFFICACY OF TREATMENT
AT POPULATION LEVEL
Summary of population variation
(host and bacteria…)
Clearance x MIC90
Bioavailability
Dose =