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Pharmacokinetic and pharmacodynamic principlesfor antibiotic use in bovine respiratory disease
Lorenzo FraileCReSA Researcher (program INIA-IRTA)
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• 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
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Bovine Respiratory Disease (BRD)
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-Cough-Dyspnoea-Abdominal breathing
Symptoms Population level -Mortality-Morbidity
-Growth retardation-Increase feed conversion ratio-Appearance of runts
Economic consequences
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Host
Environment
BRD etiopathogeny
Genetic background
Productivity
Production systemDensity
Microorganism
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• 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 agentThe higher the value, the most relevant is.
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Mechanisms of action of antibiotics
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Mechanisms of action of antibiotics
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Pharmacokinetics and Pharmacodynamics. A brief overview.
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Host
Drug Microorganisms(Bug)
Susceptibility
Pharmacodynamics
Infection
Immune systemToxicityPharm
acokinetic
s
Do we really know how antibiotics are applied?
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• 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)
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PK parameters
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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)
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Pharmacodynamics parameters
Watts et al, J Clin Microbiol. 1994
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Treatment of pneumonic disease
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Where is the pathogen?Pharmacokinetic: Where???• Plasma• Lung homogenate• Bronchoalveolar lavage• Pulmonary Epithelial Lining Fluid (PELF)
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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”…
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Posology regimen of antibiotics
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• 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?
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Fluoroquinolone and Mannhemia haemolytica
Concentration dependent
Concentration-dependent antibiotics
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Time-dependent antibiotic
An increase in concentration
It does not imply a quickerdecrease of the bacterial load
Cephalosporin of human use
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Azithromycin (a human case)
Time-dependent antibiotic
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Classical concept of antibiotic treatment
It is true for macrolides (classical) and Beta-lactam antibiotics
MIC
Clearance x MIC90Bioavailability
Dose =
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PK/PD parameters
Threshold values:
AUC0--24:MIC = 125Cmax:MIC = 10T (inter-dosing interval)>(1-5)* MIC= 40-100%
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Are all the antibiotics similar?• Bactericidal versus bacteriostatic
Only indicative. It must be studied each antimicrobial with each bacteria
Action Group ExamplesMainly bacteriostatic Phenicols
MacrolidesLincosamidesTetracyclines
FlorfenicolTiamulin
LincomycinDoxycycline
Mainly bactericidal time-dependent
PenicillinCephalosporins
CefquinomeCeftiofur
AmoxicillinMainly bactericidal
concentration-dependent with
relevant post-antibiotic action
AminoglycosidesFluoroquinolones
MarbofloxacinEnrofloxacin
AmikacinStreptomycin
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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
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Dose determination studies
Dose ResponseBlack box
PK/PD
Dose
PK PD
Plasmatic concentration
surrogate
Response
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• 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
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“Response”“Exposure”
• Concentration/time profile
• AUC • Cmax , Cmin
• “Biomarker” (Acute phase proteins)
• Clinical end-point
PK/PD models
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What about the end-point?
0
30
60
90
0 0.5 2 16 64Dose (mg/kg)
Res
pons
e %
Mortality
Bacterial excretion Ceftiofur
N = 383 cerdos
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• 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
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Application of antibiotic therapy to the treatment of BRD
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• 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)
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• 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)
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• To be studied:– age (pre-ruminant vs. ruminant)– type of production/facilities– breed– gestation/lactation– disease– management/nutrition
Population pharmacokinetics
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• 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
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Variability is a biological fact …
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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)
Con
cent
ratio
ns m
g/m
L
Doxycycline 20 mg/Kg body weight/day by drinking water
Interindividual pharmacokinetic variability
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00.20.40.60.81.01.21.4
0 1 2 3 4 5 6Sample time
Con
cent
ratio
ns (µ
g/m
L)
Interindividual pharmacokinetic variability
Amoxycillin 500 ppm by feed
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• To know the variation of key pharmacokinetic parameters inside a population.– clearance (media and standard deviation)– bioavailability
• To know the variation of key pharmacodynamicparameters (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 MIC90Bioavailability
Dose =
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