3. pharmacokinetic and pharmacodynamic priniciples for antibiotic us in brd

Pharmacokinetic and pharmacodynamic principlesfor antibiotic use in bovine respiratory disease

Lorenzo FraileCReSA Researcher (program INIA-IRTA)

• 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

Bovine Respiratory Disease (BRD)

-Cough-Dyspnoea-Abdominal breathing

Symptoms Population level -Mortality-Morbidity

-Growth retardation-Increase feed conversion ratio-Appearance of runts

Economic consequences

Host

Environment

BRD etiopathogeny

Genetic background

Productivity

Production systemDensity

Microorganism

• 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.

Mechanisms of action of antibiotics

Mechanisms of action of antibiotics

Pharmacokinetics and Pharmacodynamics. A brief overview.

Host

Drug Microorganisms(Bug)

Susceptibility

Pharmacodynamics

Infection

Immune systemToxicityPharm

acokinetic

s

Do we really know how antibiotics are applied?

• 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)

PK parameters

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)

Pharmacodynamics parameters

Watts et al, J Clin Microbiol. 1994

Treatment of pneumonic disease

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

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”…

Posology regimen of antibiotics

• 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?

Fluoroquinolone and Mannhemia haemolytica

Concentration dependent

Concentration-dependent antibiotics

Time-dependent antibiotic

An increase in concentration

It does not imply a quickerdecrease of the bacterial load

Cephalosporin of human use

Azithromycin (a human case)

Time-dependent antibiotic

Classical concept of antibiotic treatment

It is true for macrolides (classical) and Beta-lactam antibiotics

MIC

Clearance x MIC90Bioavailability

Dose =

PK/PD parameters

Threshold values:

AUC0--24:MIC = 125Cmax:MIC = 10T (inter-dosing interval)>(1-5)* MIC= 40-100%

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

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

Dose determination studies

Dose ResponseBlack box

PK/PD

Dose

PK PD

Plasmatic concentration

surrogate

Response

• 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

“Response”“Exposure”

• Concentration/time profile

• AUC • Cmax , Cmin

• “Biomarker” (Acute phase proteins)

• Clinical end-point

PK/PD models

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

• 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

Application of antibiotic therapy to the treatment of BRD

• 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)

• 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)

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

Population pharmacokinetics

• 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

Variability is a biological fact …

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

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

• 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 =