in vivo PKPD efficacy indices Alain BousquetMélou May 2023 PHARMACODYNAMICS PKPD approach for antibiotics What information is needed available Therapeutic effect ID: 1036398
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1. PK/PD for antibiotics The in vivo PK/PD efficacy indicesAlain Bousquet-Mélou May 2023
2. PHARMACODYNAMICSPK/PD approach for antibioticsWhat information is needed/available ? Therapeutic effectPHARMACOKINETICSABSORPTIONELIMINATIONDISTRIBUTIONPlasmaconcentrationsDose of active ingredientadministeredInfectious siteconcentrationsin vitro PDMICRates of bacterial killingin vivo PKPK dataPK/PD efficacy indices
3. Because they control the concentrations at the infection site where pathogens are locatedWhy plasma concentrations ?
4. Where are the pathogens located? Most of pathogens are extracellular Streptococcus pneumoniaeEscherichia coliKlebsiella pneumoniaeMannheimia haemolyticaPasteurella multocidaActinobacillus pleuropneumoniaeMycoplasma hyopneumoniaeBordetella bronchisepticaIntracellular pathogens (optional)Rhodococcus equiStaphylococcus aureusEscherichia coliSalmonella typhiListeriaMycobacterium tuberculosisStreptococcus suisIntracellular pathogens (mandatory)ChlamydiaRickettsiaBrucellaLawsonia intracellularis
5. ATB BoundATB FreeECF = ExtraCellular FluidDiffusion/permeabilityBacteriaATB BoundATB freeThe free plasma concentrations of the antibiotic control the concentrations of the extracellular biophase !!! EXCEPT if barriers !!!Physiological: brain, prostate, eye (posterior chamber)Pathological : clot, abscess, ...BloodBinding to plasma proteins (fu)When bacteria are intracellular :The volume of distribution (Vd) is to consider
6. Tissue concentrationsFor PK/PD approach/modelling, it is mandatory to consider free concentrations In vitro, in standard broth, there is no bindingthe assessed activity by MIC or time-kill curves is the activity of the free drugThe in vitro activity needs then to be compared to free plasma/tissular concentrations to predict efficacy of the treatment
7. The in vivo PK/PD efficacy indicesWay to standardize plasma exposure, according to the pathogen susceptibility (MIC)Plasma exposure in terms of Intensity and/or DurationThreshold values of these indices "guarantee" the cure with a certain probability (usually 80-90%)
8. Step 1 : To identify the more relevant PK/PD index for the drugStep 2 : To determine the value of this PK/PD index that needs to be reached to ensure efficacy The in vivo PK/PD efficacy indices
9. Plasma concentrationsTimeTime > MIC (T > MIC)Peak / MIC (Cmax /MIC)Area24h under the curve / MIC(AUC24h / MIC)MICIntensityDurationThe in vivo PK/PD efficacy indices
10. The PK/PD index best correlated with efficacy depends on the antibiotic class
11. Relationship between 3 PK/PD indices and Streptococcus pneumoniae counts after 24 h of treatment with temafloxacinAndes & Craig, Int J Antimicrob Agents, 2002Mouse modelThigh infectionNeutropenic animalsFluoroquinolone
12. Relationship between 3 PK/PD indices and Klebsiella pneumoniae counts after 24 h of treatment with ceftazidimeAndes & Craig, Int J Antimicrob Agents, 2002Mouse modelThigh infectionNeutropenic animalsBeta-lactam
13. Antibacterial actionAntibiotic familyPK-PD index correlated with antibacterial action Concentration-dependentAminoglycosidesCmax/MICFluoroquinolonesAUC/MICCmax/MICNitroimidazolesAUC/MICCmax/MICPolymixinsAUC/MICTime-dependentPenicillinsT>MICCephalosporinsT>MICMacrolidesT>MIC or (AUC/MIC)LincosamidesT>MICPhenicolsT>MICSulfonamidesT>MICDiaminopyrimidinesT>MICBoth Time- and Concentration-dependentTetracyclinesAUC/MICKetolidesAUC/MICGlycopeptidesAUC/MIC
14. PK/PD index values required to ensure maximum efficiencyDetermination from animal modelsStep 1
15. Influence of the bacteria on the value of the PK/PD indexFor E. coli=> efficacy is maximal when T>MIC > 80% of the dosing intervalFor S. aureus=> efficacy is maximal when T>MIC >50% of the dosing intervalVogelman et al. 1988, J. Inf. Dis.E. coliS. aureusT > MIC (% assay range)Mean D log10 CFU per mouse over 24h050100050100Cefazolin
16. Influence of the immune system on the value of the PK/PD indexNeutropenicImmunocompetentHigherLowerThreshold value
17. Validation from clinical trialsPK/PD index values required to ensure maximum efficiencyStep 2
18. Clinical validationfT>MIC > 50% of the dosing interval to achieve bacteriological cure in 80% of patientsBacteriological cure versus Time > MIC when treating otitis media with beta-lactams (Craig and Andes 1996) S. pneumoniaePenicillincephalosporinsH. influenzaePenicillincephalosporinsTime above MIC (%)Bacteriological cure (%)100500050100
19. 246810126080100Relationship between Cmax/MIC ratio and clinical cure in 236 patients with Gram-negative infections treated with aminoglycosides (gentamicin, tobramycin, amikacin) (Moor et al. 1984 J. Infect. Dis).Maximum peak/MIC ratioResponse rate (%)Clinical validationfCmax /MIC > 8 to achieve bacteriological cure in 80% of patients
20. Pulmonary infections (nosocomial) treated with ciprofloxacin IVAUC/MIC was strongly predictive of - the bacterial eradication and - the time to achieve itAUC/MIC>125: very high % eradicationAUC/MIC>250: eradication obtained on the first day of treatment1005004812Days after start of therapy% patients remaining culture positiveSchentag Symposium, 1999AUC/MIC < 125AUC/MIC 125-250AUC/MIC > 250Clinical validation
21. AUC / MIC : 125 h Cmax / MIC : 8-10T>MIC :40 to 50% for Gram + bacteria 60 to 80% for Gram - bacteriaSummary of validated critical values in human medicineThese indices and their threshold values are used as indicators to predict whether a dosage will be associated with a high percentage of curePossible uses of these valuesTo check if a given dosage allows to reach these thresholds for different MIC valuesTo define, in a rational way, the administration schemeTo calculate the dosage that will allow to reach these thresholds
22. Antibacterial actionAntibiotic familyAntibioticPK-PD index correlated with antibacterial action Concentration-dependentAminoglycosidesStreptomycin, Neomycin, Gentamicin, Amikacin, TobramycinCmax/MICFluoroquinolonesEnrofloxacin, Danofloxacin, Marbofloxacin, Difloxacin, IbafloxacinAUC/MICCmax/MICNitroimidazolesMetronidazoleAUC/MICCmax/MICPolymixinsColistinAUC/MICTime-dependentPenicillinsBenzylpenicillin, Cloxacillin, Ampicillin, Amoxicillin, CarbenicillinT>MICCephalosporinsCeftiofur, Cefalexin, CefapirinT>MICMacrolides & triamilidesTilvalosin, Tylosin, Erythromycin, Tilmicosin, TulathromycinT>MIC or (AUC/MIC)LincosamidesClindamycinT>MICPhenicolsChloramphenicol, FlorphenicolT>MICSulfonamidesSulfadoxine, SulfadiazineT>MICDiaminopyrimidinesTrimethoprimT>MICBoth Time- and Concentration-dependentTetracyclinesOxytetracycline, Chlortetracycline, DoxycyclineAUC/MICKetolidesAzithromycin, ClarithromycinAUC/MICGlycopeptidesVancomycinAUC/MIC
23. Antibacterial actionAntibiotic familyAntibioticPK-PD index correlated with antibacterial action Concentration-dependentAminoglycosidesStreptomycin, Neomycin, Gentamicin, Amikacin, TobramycinCmax/MICFluoroquinolonesEnrofloxacin, Danofloxacin, Marbofloxacin, Difloxacin, IbafloxacinAUC/MICCmax/MICNitroimidazolesMetronidazoleAUC/MICCmax/MICPolymixinsColistinAUC/MICTime-dependentPenicillinsBenzylpenicillin, Cloxacillin, Ampicillin, Amoxicillin, CarbenicillinT>MICCephalosporinsCeftiofur, Cefalexin, CefapirinT>MICMacrolides & triamilidesTilvalosin, Tylosin, Erythromycin, Tilmicosin, TulathromycinT>MIC or (AUC/MIC)LincosamidesClindamycinT>MICPhenicolsChloramphenicol, FlorphenicolT>MICSulfonamidesSulfadoxine, SulfadiazineT>MICDiaminopyrimidinesTrimethoprimT>MICBoth Time- and Concentration-dependentTetracyclinesOxytetracycline, Chlortetracycline, DoxycyclineAUC/MICKetolidesAzithromycin, ClarithromycinAUC/MICGlycopeptidesVancomycinAUC/MICDaily doseshigh / uniqueAdministration schemesDaily dosesfractionated / infusionor(Very) long-action
24. 0 20 40 60 80 100 120 0 12 24 36 48 0 20 40 60 80 100 120 0 12 24 36 48 Dose 1; t = 24hFirst proposal : 2 x Dose 1; t = 24hDose 1; t = 24hSecond proposal Dose 1; t = 12hExample of a time-dependent antibioticObjective: To maximize T>MICAdministration schemes
25. Calculation of the doseExample of a concentration-dependant antibioticObjective: To have AUC/MIC equal to 125hDo you agree ?Don’t we forget something ?
26. Calculation of the doseExample of a concentration-dependant antibioticObjective: To have AUC/MI equal to 125hMIC is a free (unbound) conc.
27. To summarizeThe PK/PD index values associated with a high probability of cure:Depends on various factors: bacteria (Gram+ vs Gram-), antibiotics (beta-lactams), infectious sites, hosts (immune system)The PK/PD index correlated with efficacy:Is the same regardless of the infected host: animals, humansDepends on the killing rate of the antibioticExposure intensity (AUC/MIC, Cmax/MIC) for concentration-dependent antibiotics andExposure duration (T>MIC) for time-dependent antibioticsKnowledge of the type PK/PD indices correlated with efficacy allows optimization of dosing regimens:Maximize the intensity of exposure for concentration-dependent antibiotics Maximize the duration of exposure for time-dependent antibiotics