3. pharmacokinetic and pharmacodynamic priniciples for antibiotic us in brd

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3. pharmacokinetic and pharmacodynamic priniciples for antibiotic us in brd

  1. 1. Pharmacokinetic and pharmacodynamic principles for antibiotic use in bovine respiratory disease Lorenzo Fraile CReSA Researcher (program INIA-IRTA)
  2. 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. 3. Bovine Respiratory Disease (BRD)
  4. 4. -Cough -Dyspnoea -Abdominal breathing Symptoms Population level -Mortality -Morbidity -Growth retardation -Increase feed conversion ratio -Appearance of runts Economic consequences
  5. 5. Host Environment BRD etiopathogeny Genetic background Productivity Production system Density Microorganism
  6. 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. 7. Mechanisms of action of antibiotics
  8. 8. Mechanisms of action of antibiotics
  9. 9. Pharmacokinetics and Pharmacodynamics. A brief overview.
  10. 10. Host Drug Microorganisms (Bug) Susceptibility Pharmacodynamics Infection Im m unesystem ToxicityPharmacokinetics Do we really know how antibiotics are applied?
  11. 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. 12. PK parameters
  13. 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. 14. Pharmacodynamics parameters Watts et al, J Clin Microbiol. 1994
  15. 15. Treatment of pneumonic disease
  16. 16. Where is the pathogen? Pharmacokinetic: Where??? • Plasma • Lung homogenate • Bronchoalveolar lavage • Pulmonary Epithelial Lining Fluid (PELF)
  17. 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. 18. Posology regimen of antibiotics
  19. 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. 20. Fluoroquinolone and Mannhemia haemolytica Concentration dependent Concentration-dependent antibiotics
  21. 21. Time-dependent antibiotic An increase in concentration It does not imply a quicker decrease of the bacterial load Cephalosporin of human use
  22. 22. Azithromycin (a human case) Time-dependent antibiotic
  23. 23. Classical concept of antibiotic treatment It is true for macrolides (classical) and Beta-lactam antibiotics MIC Clearance x MIC90 Bioavailability Dose =
  24. 24. PK/PD parameters Threshold values: AUC0--24:MIC = 125 Cmax:MIC = 10 T (inter-dosing interval)>(1-5)* MIC= 40-100%
  25. 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. 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. 27. Dose determination studies Dose Response Black box PK/PD Dose PK PD Plasmatic concentration surrogate Response
  28. 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. 29. “Response”“Exposure” • Concentration/time profile • AUC • Cmax , Cmin • “Biomarker” (Acute phase proteins) • Clinical end-point PK/PD models
  30. 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. 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. 32. Application of antibiotic therapy to the treatment of BRD
  33. 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. 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)
  35. 35. • To be studied: – age (pre-ruminant vs. ruminant) – type of production/facilities – breed – gestation/lactation – disease – management/nutrition Population pharmacokinetics
  36. 36. • 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
  37. 37. Variability is a biological fact …
  38. 38. 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
  39. 39. 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
  40. 40. • 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 =

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