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Antimicrobial therapy in horses: a pharmacologist perspective. Pierre-Louis Toutain National Veterinary School; Toulouse ,France 30th October 2014; Department of Veterinary Disease Biology University of Copenhagen. Steps for a rationale selection of an antimicrobial (AM) drug. - PowerPoint PPT Presentation
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Antimicrobial therapy in horses: a pharmacologist perspective
Pierre-Louis ToutainNational Veterinary School; Toulouse ,France
30th October 2014; Department of Veterinary Disease Biology
University of Copenhagen
Steps for a rationale selection of an antimicrobial (AM) drug
1. Identity of the affecting MO2. In vitro AM susceptibility of the bug3. Nature and site of infection4. The pharmacokinetic (PK) characteristics of the
selected AM5. The pharmacodynamics (PD) properties of the
selected AM6. PK and PD integration (PK/PD indices)7. Safety issues8. Cost of the therapy
1-Why plasma concentrations are relevant for AMD and why to
compare free plasma concentration to MICs?
Nature and site of infectionWhere are located the pathogens
Extra Cellular FluidMost bacteria of clinical interest- respiratory infection- wound infection- digestive tract inf.
Cell(in phagocytic cell most often)• Legionnella spp• mycoplasma (some)• chlamydiae• Brucella• Cryptosporidiosis• Listeria monocytogene• Salmonella• Mycobacteria• Rhodococcus equi
BoundBound
Free±MIC
Free MO
2-The right dosage regimen to control the efficacious
plasma concentration
What are the elements of a dosage regimen
• The dose–A PK/PD variable
• The dosing interval• The treatment duration
–When to start–When to finish
8
A fundamental relationship
A dose can be determined rationally using a PK/PD approach
!
PKPKPD
X MICPD
X MIC
PK(0 to 1)
PK(0 to 1)
PK(0 to 1)
PK(0 to 1)
Question: what is the daily dose for enrofloxacin for different possible MIC90
• What we know:– Plasma clearance: 2.5L/Kg/24h– Bioavailability by intragastric route of 80%– Extent of binding of ~ 20%– MIC90
– The PK/PD index for optimization: AUC/MIC=125• Or equivalently : the average plasma concentration over the dosing interval
should be 5 folds the MIC
MO µg/mLE. Coli ; S. aureus 0.25
Pseudomonas aeruginosa 0.50Strept. zooepidemicus 1.00
Rhodococcus equi 2.00
It has been developed surrogates indices (predictors) of antibiotic efficacy taking into account MIC (PD) and exposure antibiotic
metrics (PK)
Practically, 3 indices cover all situations:•AUC/MIC •Time>MIC• Cmax/MIC
Practically, 3 indices cover all situations:•AUC/MIC •Time>MIC• Cmax/MIC
Recommandations thérapeutiques en fonction de la bactéricide
Pattern de la bactéricidie
Antibiotiques Objectifs
therapeutiques
Paramètre
PKPD
Type I
Concentration dépendant & effets
prolongés
Aminoglycosides
Quinolones
Optimiser les concentrations
Cmax/MIC
24h-AUC/MIC
Type II
Temps dépendant & pas de
rémanence
Pénicillines
Céphalosporines
Optimiser la durée
d’exposition
T>MIC
Type III
Temps dépendant & effets rémanents
dose-dépendant
Macrolides
Tétracyclines
Optimiser les quantités (doses)
24h-AUC/MIC
The dose for enrofloxacin
MO MIC: µg/mLE. Coli ; S. aureus 0.25
Pseudomonas aeruginosa 0.50Strept. zooepidemicus 1.00
Rhodococcus equi 2.00
The dose for enrofloxacinAUC/MIC=125
MO MIC (µg/mL) Dose (mg/kg)
E. Coli ; S. aureus 0.25 4.9
Pseudomonas aeruginosa 0.50 9.77
Strept. zooepidemicus 1.00 19.5
Rhodococcus equi 2.00 39.1
3-Variability of plasma clearance in horses
15
Drugs, ageDrugs, age
16
AMD: plasma clearancesLow or high?Low or high?
Drug ClB
(mL/kg/min)Sulphadoxine 0.32Gentamicin 1.2
Sulphamethoxazole 1.2Amikacin 1.23
Oxytetracycline 1.25Rifampin 1.34
Sulphadiazine 1.45Cefoxitin 1.72
Metronidazole 1.97Enrofloxacin 2.33
Ampicillin 2.89Ticarcillin 3.1
Amoxicillin 4.55
Drug ClB
(mL/kg/min)Trimethoprim 5.03
Ceftriaxone 5.22Cafazolin 5.27Cefadroxil 6.95Penicillin 8.5
Chloramphenicol 8.8Ciprofloxacin 9.7; 18
Clarithromycin 21.1Erythromycin 26.6
17
AMD: plasma clearancesEffect of ageEffect of age Effect of breed, fever, sex, ….Effect of breed, fever, sex, ….
A foal is not only a small horse
18
AMD: protein binding
Low or high?Low or high?• MIC are free concentrations• Only the free concentration is active• No example of drug/drug interaction
leading to increase the free drug concentration by displacement (eg with NSAID)
• MIC are free concentrations• Only the free concentration is active• No example of drug/drug interaction
leading to increase the free drug concentration by displacement (eg with NSAID)
19
AMD: bioavailability
Low or high?Low or high?
Large influence of the route of administration and of the formulations
Large influence of the route of administration and of the formulations
• Bioavailability quantifies the proportion
of a drug that is absorbed and
available to produce its systemic effect
– Extent (overall exposure)
– Rate (T>MIC)
Bioavailability
Bioavailability
Definition• Absolute
– amount of administered drug which enters the systemic (arterial) circulation and the rate at which the drug appears in the blood stream
• Relative– to compare formulations (bioequivalence)– to compare routes of administration
IV route of administrationby definition F=100%
22
Not always the case for AMD administered as prodrug such as esters as erythromycin estolate
Not always the case for AMD administered as prodrug such as esters as erythromycin estolate
Oral route of administration
24
Oral route: several possible modalities
25
Intragastric
Perlingual
Mash
Fed vs unfed (food withheld for 12h )Fed vs unfed (food withheld for 12h )
Oral enrofloxacin : no food effect
Steinman et al JPT 2006
5 mg/kg
Fasted Hay concentrateAUC
(µg.h/ml) 18.5 12.5 13.9
T1/2 (h) 8.1 7.6 7.9
Cmax (µg/ml) 1.7 1 1.3
Rifampin administration before and after feeding
The Royal Veterinary College Peter Lees July 2003
Bioavailability: 68% (fasted) vs 26% (fed)28
Influence of food on the F% of erythromycin (base)
29
Food withheld=26% (6-44%)
Fed =7.7% (1-18%)Fed =7.7% (1-18%)
Lakritz et al AJVR, Vol 61, No. 9, September 2000
Foals should be given ERY before they are fed hay. Administrationof ERY to foals from which food was withheld overnight apparently provides plasma concentrations of erythromycin A that exceed the minimum inhibitory concentration of Rhodococcus equi for approximately 5 hours. The dosage of 25 mg/kg every 8 hours, PO, appears appropriate.
Foals should be given ERY before they are fed hay. Administrationof ERY to foals from which food was withheld overnight apparently provides plasma concentrations of erythromycin A that exceed the minimum inhibitory concentration of Rhodococcus equi for approximately 5 hours. The dosage of 25 mg/kg every 8 hours, PO, appears appropriate.
Why a possible low oral bioavailability
• Poor stability in the stomach– pH effect
• Poor absorption– Physiological origin– Binding to cellulosis
• Hepatic first-pass effect– Can be predicted from the blood clearance
• Drug interaction
31
In vitro binding (%) of TMP and sulphachlorpyridazine to hay, grass silage and concentrate
Medium(3h at 37C)
% Binding Trimethoprim
% Binding Sulphachlorpyridazine
Concentrations 4 mg/ml 100 mg/ml 4 mg/ml 100 mg/ml
Hay 82 63 90 67
Grass silage 73 47 71 33
Concentrate 64 36 86 64
Van Duijkeren, 1996
The pH effect(stomach)
33
Poor stability of the AM in the stomach: the case of erythromycin
• Inactivated by gastric acid thus:– Enteric-coated formulations – Esters (prodrugs) with improved acid stability but
requiring hydrolysis by esterases• Estolate• Stearate• ethyl succinate
34
However a horse and a man can be different and extrapolation misleading
However a horse and a man can be different and extrapolation misleading
35
Gastric pH
Time0
1
2
3
4
5
6
7
pH
Time0
1
2
3
4
5
6
7
8
pH
FastedLow pH (average of 1.6)Continuous secretion
FastedLow pH (average of 1.6)Continuous secretion
Hay ad libitumBuffering capacity of hay and saliva (at each peak)Hay ad libitumBuffering capacity of hay and saliva (at each peak)
Erythromycin: bioinequivalence of the different forms
• Three possible forms for an oral administration– Erythromycin base– Erythromycin salt (lactobionate, phosphate…)– Erythromycin esters absorbed by the GIT (estolate,
etylsuccinate)– Erythromycin ester hydrolysed in the GIT (stearate)
36
Phosphate (salt)
Estolate(ester)
Stearate(ester)
Ethylsuccinateester
AUC (µg*h/mL) 295 176 302 308
Cmax (µg/mL) 2.3 0.4 2 0.3
T1/2, (min) 149 145 110 221Poor
absorption Slow hydrolysis
Effect of age on bioavailability
37
Age effect: Bioavailability of IG Cefadroxil in foal
Duffee JVPT 1997 20 427
Age (months)
0.5 1 2 3 5
F% 99.6 67.6 35.1 19.5 14.4
Tmax (h) 2.1 1.6 1.6 .96 .90
38
Effect of age on bioavailability of oral penicillins in the horse
Drug F (%) In foal F (%) in adult
Penicillin V(phenoxymethyl
penicillin)16.00 2.00
Amoxycillin 36-42 5 - 10
Why a possible low oral bioavailability
• Poor stability in the stomach– pH effect
• Poor absorption– Physiological origin– Binding to cellulosis
• Hepatic first-pass effect– Can be predicted from the blood clearance
• Drug interaction
40
Poor absorption due to drug-drug interaction
Association of AMDClarithromycin ± Rifampin
• After RIF comedication, relative bioavailability of CLR decreased by more than 90%.• the drastic lowering of the average CLR plasma concentrations by more than 90% have
resulted from induction of hepatic and intestinal CYP3A4 and intestinal ABCB1 and probably
• ABCC2. efflux transport seems to be the major reason for lower bioavailability• there are many doubts from a pharmacokinetic point of view that combination therapy of CLR with
RIF might really be superior to other eradication protocols as suggested by the results of a retrospective clinical study in foals (Gigue`re et al., 2004). The absence of major drug interactions as shown in our recent pharmacokinetic study with tulathromycin and RIF should be confirmed before a combination treatment is launched in clinical practice (Venner et al., 2010).
42
Poor bioavailability due to a hepatic first-pass effect
43
The 3 segments of the digestive tract in terms of first-pass effect
44
Buccal cavityNo
first-passeffect
Small intestine/large bowelFull First pass-effect
Rectal Limited
first-pass effect
Rectal Limited
first-pass effect
Hepatic first pass effect
45• Fmax = 1 – Eh=1 - [Clh / Qh]=1-[17/24]=0.30• Fmax = 1 – Eh=1 - [Clh / Qh]=1-[17/24]=0.30
LiverFmax = 1 - Eh
Eythromycin Dose
Eh~70%Fraction eliminated by first pass effect
30%
Plasma erythromycin after an IG administration of a salt (phosphate) or an ester (estolate) of
erythromycin (food withheld)
47
Plasma clearance of erythromycin is very large (17.5ml/kg/min) suggesting a likely large hepatic first-pass effect in horse
Plasma clearance of erythromycin is very large (17.5ml/kg/min) suggesting a likely large hepatic first-pass effect in horse
F% from Phosphate:16±3.5%F% from estolate: 14.7±11%Both are very low: why?
F% from Phosphate:16±3.5%F% from estolate: 14.7±11%Both are very low: why?
Intramuscular administration
IV administration of sodium benzylpenicillin
Penicillin G potassium vs. Penicillin G procaine
Flip-flop kinetics
Procaine benzylpenicillin ( procaine penicillin) is an ester of benzylpenicillin and the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the circulation and hydrolysed to benzylpenicillin This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin.
Procaine benzylpenicillin ( procaine penicillin) is an ester of benzylpenicillin and the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the circulation and hydrolysed to benzylpenicillin This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin.
Influence of the injection site on bioavailability of Penicillin (administration of procaine benzylpenicilin)
Influence of the injection site on bioavailability of Penicillin (administration of procaine benzylpenicilin)
Semi-membrane / semi-tendineux
0 2 4 6 8 10 12 24h
(Time)0
1
2
3
4
Con
cent
ratio
ns (
UL/
mL)
M. serratusM. bicepsM. pectoralisM. gluteusM. Subcutaneous
Firth et al. 1986, Am. J. Vet. Res.
Terminal half-life and bioavailability of procaine benzylpenicillin in the horse
Injection site Terminal half-life (h) Bioavailability (%)
Subcutaneous 21.8 78.4Intramuscular :
M.gluteus 12.8 78.4M.pectoralis 14.9 94.2
M.biceps 14.9 97.6M.serratus 8 113.2Intravenous 3.72 100
The terminal half-life is much more longer after an extravascular administration:The so-called flip-flop phenomenon
Intra- vs intermuscular administrationIntra- vs intermuscular administration
• The best site for IM administration is the 5th
cervical vertebra, ventral to the funicular part of the ligamentum nuchae but dorsal to the brachiocephalic muscle
Boyd et al,1987, Vet. Rec.
True IM
3Preanalytical method 06 - 54
Intra- vs intermuscular administrationIntra- vs intermuscular administration• Injection in the 4th space but the ventral injection
has traversed to the 6th vertebral space
Boyd et al,1987, Vet. Rec.
Procaine penicillin adverse effects
• PP is associated with incidence of severe adverse reactions with distress…...but much less frequently with water-soluble salts of Penicillin.– Anaphylactic reaction: rare in horses
• Penicillin have affinity to proteins and may form hapten• Hypersensitivity is the most common cause of negative
reaction to penicillin
– Procaine toxicity: frequent in horses• Due to action of the free procaine on the CNS
56
Procaine penicillin adverse effects• Procaine is hydrolysed by plasma esterase to
non toxic metabolite (Para-aminobenzoic acid and Diaminoethanol)
• Toxicity is observed if the rate of Procaine absorption exceeds the hydrolyzing capacity– Inadvertent IV route after an IM administration– Poor esterase activity (next slide)– Some formulations have high free procaine
concentration (vehicule) and this is increase by high room temperature (stability issue)
57
PP adverse effects: esterase activity
58
Poor esterase activity in horses havingADRPoor esterase activity in horses havingADR
The question of medication/doping control for penicillin procaine
• Normally, no routine screening for doping control for the AMD
• But procaine is controlled (as a local anesthetic)– What about penicillin procaine? – Can be very long in urine (several months)
Local tolerance of AMD• Poorly tolerated
– aminoglycosides– TMP/sulfate– macrolides– tétracyclines
• Well tolerated– Penicillines (peni-procaine better than
penicillin G)
Inhalation
63
Cortic 00A.64
Many devices: are they equivalent?
Cortic 00A.65
Cefquinome inhalation:high local concentration
• Very high local drug concentrations of cefquinome was achieved in horses using a jet nebulizer, but cefquinome was not detectable after 4 h in the majority of horses– This is likely true for any drug that was not
specifically developed for inhalation (e.g. dexamethasone) because pulmonary absorption is very fast due to a very high blood flow.
66
Inhalation treatment: an user safety issue?
• During exhalation, some degree of air pollution of the drug was evident and user safety was accounted for by ventilating the room sufficiently during administration
67
Drug elimination and PK selectivity
Selectivity of antimicrobial drugs in veterinary medicine
Almost all oral and parenterally administered antimicrobials have been linked with antimicrobial associated diarrhoea (AAD) in both man and horses, although some antimicrobials clearly pose a higher risk:•Macrolides ( erythromycine, tylosine, …)•Tetracyclines (doxycyclin, OTC…)•Bêtalactams (Penicillin G, ampicillin, ceftiofur..)
Almost all oral and parenterally administered antimicrobials have been linked with antimicrobial associated diarrhoea (AAD) in both man and horses, although some antimicrobials clearly pose a higher risk:•Macrolides ( erythromycine, tylosine, …)•Tetracyclines (doxycyclin, OTC…)•Bêtalactams (Penicillin G, ampicillin, ceftiofur..)
AMD effect on the enteric anaerobes
• The potential of an antimicrobial to induce AAD is largely dependent on its effect on the enteric anaerobes, which in turn reflects its spectrum of antibacterial activity, and the concentration of active drug within the intestine– lincosamides, macrolides and b-lactams
have efficacy against anaerobes
Factors determining AMD concentration in the gut
• the route of administration– IV vs. oral for oxytetracyclines
• the % of drug absorbed from the intestine – Low bioavailability of many AMD– Food effect
• The % excreted in bile or mucus– Macrolides (bile), doxycycline (enterocytes)– Large differences between quinolones (enro vs. cipro)
• The extent to which the drug is inactivated by the intestinal contents
• Anecdotally, there appear to be geographical differences in the susceptibility of the local equine population to develop AAD after administration of a particular antimicrobial
• This mayreflect regional differences in the composition of the enteric flora
Both hospitalisation and the use of AMD were associated with prevalence of AMR among E coli isolated from the feces of horse (Dunowska at al JAVMA 2006 228 1909Both hospitalisation and the use of AMD were associated with prevalence of AMR among E coli isolated from the feces of horse (Dunowska at al JAVMA 2006 228 1909
Pharmacodynamic of antibiotic in horses
76
A fundamental relationship
A dose can be determined rationally using a PK/PD approach
!
PKPD
X MICPD
X MIC
PK(0 to 1)
PK(0 to 1)
CLSI breakpoints for the horse 2014(µg/mL)
Conditions Antibiotics Pathogens S I R Comments
Gentamicin
Enterobacteriaceae ≤2 4 ≥8 Breakpoints derived from microbiological, pharmacokinetic (using accepted clinical doses), and pharmacodynamic data. For horses, the dose of gentamicin modeled was 6.6 mg/kg
every 24 hours, IM.Pseudomonas aeruginosa ≤2 4 ≥8
Actinobacillus spp. ≤2 4 ≥8
Horses Respiratory Disease Ampicillin
Streptococcus equi subsp. ≤0.25
For horses, the dose of ampicillin sodium modeled was 22 mg/kg IM every 12 hourszooepidemicus and
subsp. equi ≤0.25
Horses (Respiratory, Soft Tissue) Penicillin
Staphylococcus spp. ≤0.5 1 ≥2 Breakpoints derived from microbiological, pharmacokinetic data (using accepted clinical, but extra-label doses), and pharmacodynamic data. The dose of procaine penicillin G modeled was 22 000 U/kg, IM, every 24 hours.Streptococcus spp. ≤0.5 1 ≥2
Horses (respiratory, genital tract) Cefazolin
Streptococci – β-hemolytic group Escherichia coli
≤2 4 ≥8
Cefazolin breakpoints were determined from an examination of MIC distribution of isolates and PK-PD analysis of cefazolin. The dosage regimen used for PK-PD analysis of cefazolin was 25 mg/kg administered every six hours intravenously in horses and dogs.
Horses Respiratory Disease Ceftiofur Streptococcus equi
subsp. zooepidemicus ≤0.25
In vitro veritas
MICs estimated with different inoculmum densities, relative to that MIC at 2x105
Ciprofloxacin
Gentamicin
Linezolid
Daptomycin
Oxacillin
Vancomycin
In vitro veritas?
Evaluation of tulathromycin in the treatment of pulmonary abscesses (Rhodococcus equi) in foals
Venner et al Vet J 2006
Azithromycin+RifampinAzithromycin+RifampinTulathromycinTulathromycin
The combination of a macrolide and rifampin is synergistic both in vitro and in vivo, and the use of the 2 classes of drugs in combination reduces the likelihood of R. equi esistance to either drugThe combination of a macrolide and rifampin is synergistic both in vitro and in vivo, and the use of the 2 classes of drugs in combination reduces the likelihood of R. equi esistance to either drug
Tulathromycin: MIC (ng/mL) in MHB vs. calf serum25%,50%,75% and 100%
25% 50% 75% 100 %
The serum effect
For azithromycin (closely related to tulathromycin) the presence of 40% serum during the MIC test decreasedMICs by 26-fold for serum-resistant Escherichia coli and 15-fold for Staphylococcus aureus.
For azithromycin (closely related to tulathromycin) the presence of 40% serum during the MIC test decreasedMICs by 26-fold for serum-resistant Escherichia coli and 15-fold for Staphylococcus aureus.
Rhodococcus equi:
Clarithromycin is the macrolide of choice for foals
• Clarithromycin is the macrolide of choice for foals with severe disease, given the most favorable minimum inhibitory concentration against R equi isolates obtained from pneumonic foals (90% of isolates are inhibited at 0.12, 0.25, and 1.0 mcg/mL for clarithromycin, erythromycin, and azithromycin, respectively).
• In foals with R equi pneumonia, the combination of clarithromycin (7.5 mg/kg, PO, bid) and rifampin is superior to erythromycin-rifampin and azithromycin-rifampin.
• Foals treated with clarithromycin-rifampin have improved survival rates and fewer febrile days than foals treated with erythromycin-rifampin and azithromycin-rifampin. Reported adverse effects of clarithromycin-rifampin include diarrhea in treated foals. The duration of antimicrobial therapy typically is 3–8 wk.
In vitro veritasthe case of combination
• The combination of a macrolide (erythromycin, azithromycin, or clarithromycin) with rifampin is the recommended treatment for infection caused by R. equi, based on in vitro activity data, pharmacokinetic studies, and retrospective studies.
• The level of evidence for this recommendation is moderate, with no randomized controlled studies available to substantiate it.
Association Clarithromycin + Rifampina major PK interaction
• After RIF comedication, relative bioavailability of CLR decreased by more than 90%.• the drastic lowering of the average CLR plasma concentrations by more than 90% have
resulted from induction of hepatic and intestinal CYP3A4 and intestinal ABCB1 and probably
• ABCC2. efflux transport seems to be the major reason for lower bioavailability• there are many doubts from a pharmacokinetic point of view that combination therapy of CLR with
RIF might really be superior to other eradication protocols as suggested by the results of a retrospective clinical study in foals (Gigue`re et al., 2004). The absence of major drug interactions as shown in our recent pharmacokinetic study with tulathromycin and RIF should be confirmed before a combination treatment is launched in clinical practice (Venner et al., 2010).
87
88
La cinquième édition (2013) du livre de référence en antibiothérapie vétérinaire avec
un chapitre chez le cheval