Antibioth rapie v t rinaire et probl mes de sant publique Les facteurs de risque de l antibior sistance Le sch ma po

DownloadAntibioth rapie v t rinaire et probl mes de sant publique Les facteurs d...

Advertisement
Download Presentation
Comments
ray
From:
|  
(263) |   (0) |   (0)
Views: 74 | Added: 10-05-2012
Rate Presentation: 0 0
Description:

Antibioth rapie v t rinaire et probl mes de sant publique ...

An Image/Link below is provided (as is) to

Download Policy: Content on the Website is provided to you AS IS for your information and personal use only and may not be sold or licensed nor shared on other sites. SlideServe reserves the right to change this policy at anytime. While downloading, If for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.











- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -




2. Usages des antibiotiques

3. "One can think of the middle of the 20th century as the end of one of the most important social events in history: the virtual elimination of the infectious diseases as a significant factor in social life" Sir Mac Farland Burnett, Natural History of Infectious Disease, 1962 "The war against infectious diseases has been won" U.S. Surgeon General, 1969

4. Aujourd'hui de nombreuses maladies infectieuses qui ?taient jugul?es resurgissent ?mergence de r?sistances

5. Causes de mortalit? (2001)

6. Causes de mortalit? (WHO, 2004)

7. Causes de mortalit? infectieuse (WHO 2004)

8. Leading infectious killers

9. Les cons?quences de l'antibior?sistance Individuelles ?chec du traitement Collectives perte d'activit? de l'antibiotique ou d'une famille d'antibiotiques

10. Facteurs m?dicaux et non m?dicaux impliqu?s dans l'?mergence d'antibior?sistance

11. Facteurs non m?dicaux impliqu?s dans l'?mergence d'antibior?sistance Mondialisation de l'agriculture (?changes, transports) Intensification de l'agriculture (usage v?t?rinaire) Usages industriels d?antibiotiques Usages phytosanitaires d?antibiotiques Surpopulation, urbanisation Fr?quence et nature des contacts interindividuels Mobilit? des populations Pauvret? Facteurs climatiques (temp?rature, humidit?)

12. Facteurs m?dicaux impliqu?s dans l'?mergence d'antibior?sistance Acc?s libre aux produits de sant?, autom?dication Les g?n?riques ( augmentation de la consommation de vieux antibiotiques : ex: ciprofloxacine ) Techniques m?dicales (service d'urgence, r?animation, Sch?mas posologiques inad?quats Valeurs critiques des antibiogrammes ? r?viser Population immunod?prim?e en expansion (greff?s, sujets ?g?s, SIDA)

15. Correlation between community use and the number of trade names for oral-use agents for 6 antibacterial classes in EU

16. Generic competition for drugs availability: Is it a good medical practice to encourage the use of old antibiotics rather new ones?

17. Is it a good practice to encourage the use of old antibiotics rather new ones? Traditionally, from a public health perspective, doctor are encouraged not to employ newer drugs, but rather to use the older antibiotics. The recommendation whether to choose older rather than newer antibiotics was recently challenged on an epidemiological basis (Amyes et al., 2007) and shown to be flawed for quinolones, cephalosporins and carbapenems.

19. R?sistance en m?decine humaine Quelle est la situation?

20. Micro-organismes pathog?nes r?sistants majeurs en m?decine humaine Micro-organismes Origine animale ? S. Aureus Methicilline-resistant oui Mycobacterium tuberculosis Non (interdiction de traiter la tub en v?to) Streptococcus pneumoniae Non Streptococcus pyogenes Non Neisseria meningitidis Non Neisseria gonorrhoea Non Campylobacter spp Possible (peu d'?vidence d'?chec th?rap.) Salmonella spp Possible (peu d'?vidence d'?chec th?rap.) E coli (urogen 0157) Possible (taux de r?sistants tr?s faible) Vancomycin-resistant enterococci Peut-?tre Pseudomonas aeruginosa Non Klebsiella spp Acinetobacter spp Non Enterobacter spp Non Pneumocoque Non

22. Origine des r?sistances en m?decine humaine La plupart des r?sistance en m?decine humaine ne sont pas li?es aux usages v?t?rinaires des antibiotiques On a estim? ? environ ??4% ?? les r?sistances humaines d?origine animale et cela concerne en g?n?ral des pathog?nes peu dangereux Le cas actuel des MRSA N?anmoins, il convient de minimiser les sources animales d?antibior?sistance

23. Antibior?sistance en m?decine humaine et usage v?t?rinaire des antibiotiques

24. Consommation mondiale d?antibiotiques pour les animaux 27 000 tonnes 99% : animaux de rente 60% 15-20% 15-20% 1% 1% animaux de compagnie

25. Consommation d'antibiotiques en Europe L'Europe consomme 100 mg d'antibiotique par kg de viande produite

26. Production d?animaux sains pour fournir des denr?es animales ou d?origine animale saines, abondante et bon march?

27. Les diff?rents types d?usage des antibiotiques en m?decine collective (porc, volaille, veau?)

28. Consommation mondiale annuelle d?antibiotiques chez l?animal (tonnes) Oxyt?tracycline 5 300 Chlort?tracycline 3 900 Monensine 3 500 Bacitracine 3 200 Tylosine 2 300 Salinomycine 2 100 Lasalocide 1 800 Penicilline G 900 Narasine 700 Virginiamycine 600

30. Usages v?t?rinaires des antibiotiques et implications pour l?homme

31. Les probl?mes li?s ? l?usage des antibiotiques en m?decine v?t?rinaire Rejet d?antibiotique dans l?environnement R?sidus d?antibiotique dans les aliments Diminution de la sensibilit? ou r?sistance des pathog?nes zoonotiques passant de l?animal ? l?homme soit directement soit via la cha?ne alimentaire D?veloppement de r?sistance sur la flore commensale et passage des g?nes de r?sistance ? l?homme

32. Probl?me li?s ? l? excr?tion des antibiotiques par l?animal dans l'environnement

33. Probl?me de la pr?sence des antibiotiques dans l'environnement Certains antibiotiques sont excr?t?s sous leur forme active par l?animal ( f?ces, urine) et persister dans les lisiers et dans l?environnement Grande stabilit? de certains antibiotiques Ex:T?tracyclines : plusieurs mois dans les sols La Tiamuline reste stable dans un lisier de porc pendant plus de180 jours Le temps de demi-vie de l??rythromycine dans le lisier de porc est de 41 jours Les antibiotiques ainsi excr?t?s peuvent agir sur les flores environnementales (lisiers?) d?o? l?analyse ?co-tox r?alis?e lors des demandes d?AMM v?t?rinaires

34. R?sidus d?antibiotiques dans les aliments Issus de l?animal Non respect des d?lais d?attente Plan de surveillance de la DGAL Contamination Glace aux antibiotiques pour les poissons

35. Les probl?mes li?s ? l?usage des antibiotiques en m?decine v?t?rinaire Rejet d?antibiotique dans l?environnement Diminution de la sensibilit? ou r?sistance des pathog?nes zoonotiques passant de l?animal ? l?homme soit directement soit via la cha?ne alimentaire D?veloppement de r?sistance sur la flore commensale et passage des g?nes de r?sistance ? l?homme

36. Quels sont les germes de l?animal susceptibles de faire de la r?sistance et de poser des probl?mes ? l?homme via l?alimentation

37. Les germes susceptibles de faire de la r?sistance en MV

38. Germes zoonotiques

39. Antibior?sistance : passage directe de l?animal ? l?homme (risque non professionnel)

40. Overview of SA & MRSA in human Staphylococcus aureus (SA) is part of normal human bacterial flora, and is found primarily in the nares SA can causes serious invasive infections including endocarditis, osteomyelitis, bacteriema, pneumonia and toxic shock syndrome.

41. MRSA (SARM) Before penicillin mortality rate from invasive Staph aureus was 90% Penicillin has a dramatic effect However resistance developed Introduction of Methicillin in 1959 to the treatment of SA resistant to penicillin MRSA identified in 1961

42. MRSA as a leading cause of nosocomial infections

43. MRSA in human: nosocomial infections Major cause of morbidity and mortality in human Intensive Care Units (ICU) Up to 50% staphylococcal infections in human ICUs are now due to MRSA Transmission via transiently colonised hands of health care workers Hospital acquired strains commonly resistant to multiple classes of antibiotics

44. S. aureus : nosocomial infections in humans Superficial infections Wound infections Catheter infections Endocarditis Bacteraemia with sepsis Mortality of around 50%

45. MRSA: transmission Hand-to hand transmission From infected patients From environment Floor (27% of surface in room of MRSA positive patient) Door handles Computer etc

46. MRSA: treatment MRSA are sensitive to vancomycin, teicoplatin, nitrofurantoin, rifampicin, linezolid and quinopristin-dalfopristin;

47. MRSA: epidemiology

48. Overview of SA & MRSA in human epidemiological facts (US 2005) The standardized incidence rate of invasive MRSA was 31.8 per 100 000 persons year The standardized mortality rate was 6.3 per 100 000 and extrapolation to a national level predicted about 19000 deaths annually associated to MRSA i.e more deaths than attributed to AIDS in that year! A meta-analysis studies found that the risk of mortality due to invasive MRSA infections was approximately twofold that seen with invasive methicillin sensitive SA

49. MRSA in animals

50. SA in animals A ubiquitous commensal with a host range that span to all vertebrates In domestic animals, SA is primarily an opportunistic pathogen associated with sporadic infections, but it is a major etiological agent of bovine mastitis An Update on Staphylococcus aureus Mastitis

51. MRSA in animals

52. La transmission d?homme ? homme des germes zoonotiques

53. La transmission d?homme ? homme des germes zoonotiques Rare mais semble prendre de l?importance avec les MRSA Cela peut survenir chez les immunod?prim?s Quand la flore bact?rienne a ?t? perturb?e par un usage excessif d?antibiotique Risk assessment model (www.fda.gov/cvm/antimicrobialrisk-asses.h)

54. MRSA: transmission between animals to man Until recently, it was accepted that epidemiology of transmission and antimicrobial resistance of MRSA were essentially confined to the human arena, and that animals reservoir were of negligible importance Animal can act as reservoir of MRSA ( cat, dogs, horse, chicken, rabbit, pig, guinea pigs, turtle, parrot, etc.) Currently we have evidences of MRSA animal-to-human transmission (e.g from horse to human)

55. MRSA in horse (Ontario Vet College 2002) Asymptomatic nasal carriage of MRSA in 26 hospitalized horses and 16 vet personnel

56. MRSA: An Irish survey 2005 sampling Recovery of MRSA in animals with respiratory, urinary tract or wound infection and animal subjected to surgery following treatment in 1 vet hospital and 16 private vet clinics MRSA was recovered from 25 animals ( 14 dogs, 8 horses, 1 cat, 1 rabbit & 1 seal) and also 10 attendant vet personnel (healthy carriers)

57. sondage BVA aupr?s d'un ?chantillon de 1 009 personnes et publi? dans le num?ro de f?vrier 2002 du mensuel Trente Millions d'amis Pr?s de la moiti? (45 %) des propri?taires de chats dorment avec leur animal.

58. passage directe de l?animal ? l?homme (risque professionnel)

59. A French studies has documented antimicrobial resistance of commensals in pigs and pig farmers,

60. MRSA in swine A national Dutch survey of 540 pigs slaughtered in nine slaughterhouses, found 39% of the pigs (and 44 out of 54 groups of pigs) to be positive for MRSA in their nares. 39 All the isolates belonged to a single clonal group, MLST 398, Dutch studies estimate the prevalence of the ST398 clone in people with occupational exposure to pigs to be 760 times higher than that of the general population. investigations in other European countries (Belgium, Germany, Denmark) indicate that the occurrence of MRSA in swine is not a problem limited to the Netherlands

61. MRSA: foodborne route of transmission S aureus can frequently be isolated from pig carcasses, though generally resistant isolates have not been predominant However concerns about foodborne risk have been reinforced by the first report of a ?life threatening? infection with the ?pig? ST 398 MRSA-strain in a 63-year-old Dutch woman who was not exposed to pigs, suggesting indirect (possibly foodborne) routes of transmission.

62. MRSA in vets

63. MRSA colonization is an occupational risk for veterinary professionals

64. Resistance among coliforms isolated from fecal samples from veterinarians of different specialities resistance Pig vet Cattle vet Poultry vet Pet vet Non pract.vet Tetracyclin 17 22 42 21 10 Ampicillin 4 26 16 13 10 Personal AB consumption 15 15 30 21 0

65. ?cosyst?me et antibioth?rapie v?t?rinaire : passage indirecte de l?animal ? l?homme via l?alimentation

66. Antibior?sistance : passage indirecte de l?animal ? l?homme via l?alimentation

67. Les deux dangers de sant? publique li?s ? l?antibior?sistance La transmission de pathog?nes zoonotiques devenus r?sistants aux AB Salmonella Campylobacter E. coli La transmission de mat?riel g?n?tique support de r?sistance et capable de coloniser la flore commensale digestive humaine enterococci autres enterobacteriaciae

68. Diffusion de la r?sistance de l?animal ? l?homme Bact?ries zoonotiques Bact?ries commensales

69. Comment des bact?ries rendues r?sistantes ? cause de traitements v?t?rinaires ou encore des g?nes de r?sistance d?origine v?t?rinaire passent-ils ? l?homme?

70. Transmission ? partir de l?animal des germes zoonotiques Le traitement d'animaux porteurs de germes zoonotiques va transf?rer ? l'homme directement ou via l'alimentation des germes zoonotiques r?sistants environ 100 morts aux USA imput?s ? cette cause

71. How people get antibiotic-resistant bacteria from chickens

72. Retrait d?une AMM aux USA en 2005 pour une fluoroquinolone destin?e aux volailles

73. Bact?ries zoonotiques impliqu?es dans l'antibior?sistance Salmonella spp 95% des cas humains (USA) soit 1.4x106 cas par an sont d'origine alimentaire Campylobacter jejuni 80% des cas humains (USA) soit 2x106 cas par an sont d'origine alimentaire

74. Pr?valence des dangers microbiologiques (%) dans diff?rentes viandes Esp?ces bact?riennes Porc Bovin Volaille Salmonella spp 24 28 47 Campylobacter jejuni/coli 13 9 62 Listeria 27 29 25 E.coli 0157:47 1.5 1.1 1.5

75. TIAC: germes identifi?s

76. Causes de mortalit? d?origine alimentaire

77. Emergence of quinolone resistance in Salmonella typhimurium DT104 in UK following licensing of fluoroquinolones for use in food animals

78. Diffusion de la r?sistance de l?animal ? l?homme Bact?ries zoonotiques Bact?ries commensales

79. Quels sont les ?cosyst?mes de bact?ries commensales posant des probl?mes ? l?antibioth?rapie v?t?rinaire

80. Les ?cosyst?mes de bact?ries commensales posant des probl?mes ? l?antibioth?rapie v?t?rinaire Syst?mes ouverts et large r?servoir Tube digestif Peau Syst?me ouvert et faible r?servoir Arbre respiratoire Syst?me ferm? et faible r?servoir La mamelle

81. Le tube digestif comme r?servoir de bact?ries commensales Le plus large des r?servoirs Expos? aux antibiotiques administr?s par voie orale et ? biodisponibilit? r?duite comme les t?tracyclines chez le porc Expos? aux antibiotiques administr?s par voie g?n?rale et excr?t?s dans le tube digestif via la bile ou par s?cr?tion intestinale (fluoroquinolones) L?impact des antibiotiques sur la flore digestive est syst?matiquement ?valu? pour les nouveaux antibiotiques lors de la demande d?AMM

82. Biophases & antibior?sistance

83. Biophases & antibior?sistance

84. Germes commensaux et traitements antibiotiques

85. Les flores commensales chez l?homme Les bact?ries commensales (? la diff?rence des pathog?nes zoonotiques) sont des bact?ries r?sidentes et elles perdurent dans leur ?cosyst?me Les ?changes interhumains sont fr?quents (ce qui n?est pas le cas pour les zoonotiques) Les charges bact?riennes sont ?lev?es et associ?es avec un ?tat de bonne sant? Ici le risque est associ? ? la pr?valence de l?antibior?sistance dans les flores humaines

86. Enteroccocus spp: chevaux de Troie pour l?antibior?sistance Sont un r?servoir de g?nes de r?sistance aux AB Acquisition ais?e de g?ne de r?sistance et de leur trasfert ? d?autres esp?ces (Staphylococcus aureus, listeria monocytogene, bacillus spp).

87. Commensal bacteria A low level of resistance in the intestinal flora of food animals should be considered as a safety and quality mark for these animals

88. Les diff?rentes bact?ries surveill?es Bact?ries zoonotiques Salmonella spp, Isol?es dans diff?rents ?cosyst?mes (environnement, animaux, alimentation?) campylobacter coli and jejuni Isol?s ? l?abattoir pour les fili?res aviaire, porcine et bovine Bact?ries sentinelles (Indicator bacteria) E.coli, Enterococcus faecium and faecalis Isol?s ? l?abattoir pour les fili?res aviaire, porcine et bovine Pathog?nes propres aux animaux Isol?s d?animaux malades (bovins, porcins, volailles)

89. R?seau salmonella R?seau de 150 labo pilot? par l?AFSSA 4 secteurs : environnement, animaux, alimentation humaine et animale Plus de 3000 antibiogrammes/an Antibiogramme centralis?

90. Les bact?ries commensales indicatrices L??valuation du niveau de sensibilit? aux antibiotiques dans la flore f?cale permet d?appr?cier la pression de s?lection des AB E. coli & enterococci (Enterococcus faecium) Utilis? comme bact?rie indicatrice des Gram positif Enterococcus faecalis) Utilis? comme bact?rie indicatrices des Gram moins

91. R?sultats de la surveillance Farm 2003-2004 Rapport du programme fran?ais de surveillance de l?antibior?sistance des bact?ries d?origine anilale (Afssa Ao?t 2006) Pour conna?tre les r?sultats cliquer sur: programme fran?ais de surveillance

92. L'interdiction de l'avoparcine : un exemple de gestion des risques au niveau communautaire

93. La probl?matique L'avoparcine (additif alimentaire utilis? chez le porc et le poulet en tant qu'additif depuis 1976) et la vancomycine appartiennent ? la m?me famille des glycopeptides La vancomycine est utilis?e en m?decine humaine contre les ent?rocoques et les staphylocoques r?sistants ? la methicilline (antibiotique dit de dernier "recours")

94. D?couverte de la r?sistance ? la vancomycine 1986 : d?couverte des premi?res souches d'origine humaine d?Enterococcus faecium r?sistantes aux glycopeptides (ERG) Le transfert de r?sistance aux ent?rocoques est obtenu in vitro et in vivo chez l'animal ?tude danoise : association entre la pr?valence de la r?sistance ? la vancomycine dans des isolats de porcs et de volaille et l'usage de l'avoparcine (rien chez les bovins) avec des pr?valences de : 15% : technique d'enrichissement 2% : technique classique

95. Question soci?tale pos?e: Avoparcine et vancomycine appartenant ? la m?me famille, la suppl?mentation en avoparcine de l'alimentation animale contribue-t-elle ? la pr?sence de souches ERG chez l'homme ? La r?ponse n?a pas ?t? univoque mais les additifs ont ?t? interdits au nom du principe de pr?caution (gestion du danger et non du risque)

96. Trend in antibacterial usage and resistance in Enterococcus faecium in Denmark : Avoparcin

97. Les facteurs et pratiques ? risque en m?decine humaine

98. Facteurs de risques en m?decine humaine: Surconsommation d?antibiotiques

99. European Surveillance of Antimicrobial Consumption Outpatient antibiotic use in Europe Antimicrob Chemother 2006;doi: 10.1093/jac/dkl188

100. Outpatient antibiotic in 25 European countries in 2003*

101. Outpatient use of cephalosporins in 27 European countries in 2004*

102. Outpatient Antibiotic Use in Europe and Association with Resistance.

103. Usage de l'?rythromycine et cons?quence sur le pourcentage de r?sistance sur les streptocoques de type A

104. Facteurs de risques en m?decine humaine: mouvements de population et r?sistance ? Streptococcus pyogenes en su?de

105. Usure des antibiotiques et le non renouvellement des antibiotiques

106. Introductions of new antibiotic classes

107. Economie du d?veloppement d'un antibiotique Co?t : 400 ? 600 106 Euros Rentabilit? ? Si tr?s efficace, sera r?serv? aux h?pitaux

108. Facteurs de risques en m?decine humaine Areas associated with inadequate antimicrobial resistance intensive care units oncology bone marrow transplantation wards dialysis

109. Facteurs de risques en m?decine humaine Previous use of antibiotic is an important risk factor for nosocomial infections Prolonged stay in hospital patients become colonized by resistant bacteria Presence of invasive device endotracheal tubes, IV catheters, urinary catheters

110. Facteurs de risques en m?decine humaine: les sch?mas posologiques

111. Dosage regimen and prevention of resistance the most important risk factor is repeated exposure to suboptimal antibiotic concentrations dosage regimen should minimize the likelihood of exposing pathogens to sublethal drug levels

112. Effect on Penicillin resistance in pneumococcus isolates (n=465) of duration of b-lactam use, 6 months before swab collection

113. Sch?ma posologique et antibior?sistance Odds ratio confidence interval Oral blactams 3.0 1.1-8.3 in past 30 days Dose lower than 5.9 2.1-16.7 clinically recommended Treatment >5 days 3.5 1.3-9.3 16 children carrying penicillin-resistant pneumococcal

114. Dosage regimen and antibioresistance To design appropriate dosage regimen may be the single most important contribution of clinical pharmacology to the resistance problem over the next years which we are certain to be without significant advance for new antibiotics

115. Comment les antibiotiques favorisent-ils l?antibior?sistance

116. Resistance: m?canismes Emergence spontan?e Selection Transfer between patient Transfer from one country to another one

117. Sch?ma posologiques et pr?vention des r?sistances: le cas des quinolones

118. plt Traditional explanation for enrichment of mutants Placing MIC near the lower boundary of the selection window contradicts traditional medical teaching in which resistant mutants are thought to be selected primarily when drug concentrations are below MIC (shown in a figure taken from a book published in 2002 (2)). This distinction is important because traditional dosing recommendations to exceed MIC are likely to place drug concentrations inside the selection window where they will enrich resistant mutant subpopulations. While low drug concentrations do not enrich resistant mutants, they do allow pathogen population expansion; consequently, low drug doses indirectly foster the generation of new mutants that will be enriched by subsequent antimicrobial challenge. Placing MIC near the lower boundary of the selection window contradicts traditional medical teaching in which resistant mutants are thought to be selected primarily when drug concentrations are below MIC (shown in a figure taken from a book published in 2002 (2)). This distinction is important because traditional dosing recommendations to exceed MIC are likely to place drug concentrations inside the selection window where they will enrich resistant mutant subpopulations. While low drug concentrations do not enrich resistant mutants, they do allow pathogen population expansion; consequently, low drug doses indirectly foster the generation of new mutants that will be enriched by subsequent antimicrobial challenge.

119. Notion de concentration pr?ventive de mutants (CMP) : le cas des quinolones

120. plt Without antibiotics Blocking Growth of Single Mutants Forces Cells to Have a Double Mutation to Overcome Drug

121. Quinolone resistance: Spontaneous mutations Chromosomal mutation affecting drug permeation (alteration of efflux pump) Probability: 10-5 Point mutation: (gyrase, totpoisomerase) Probability: 10-8

122. Fr?quence de mutation et CMI pour la ciprofloxacine 5*MIC 10*MIC P. aeruginosa 10-7 10-9 S. aureus 10-6 10-9

123. plt The selection window hypothesis

124. plt Mutants are not selected at concentrations below MIC or above the MPC For emphasis we restate that as a rule mutants are not selectively enriched at drug concentrations below MIC. As an aside, we note some selective pressure exists at concentrations below the standard MIC because it measures inhibition of growth of a large number of cells (100,000). Indeed, some enrichment of mutants does occur upon repeated serial passage of a strain (6). These data stress that the bottom boundary of the window can be fuzzy. That is why we define it to be MIC(99), the minimal concentration that blocks growth of 99% of the cells in a culture. MIC(50) would be a more precise lower boundary, but it is more difficult to determine experimentally.For emphasis we restate that as a rule mutants are not selectively enriched at drug concentrations below MIC. As an aside, we note some selective pressure exists at concentrations below the standard MIC because it measures inhibition of growth of a large number of cells (100,000). Indeed, some enrichment of mutants does occur upon repeated serial passage of a strain (6). These data stress that the bottom boundary of the window can be fuzzy. That is why we define it to be MIC(99), the minimal concentration that blocks growth of 99% of the cells in a culture. MIC(50) would be a more precise lower boundary, but it is more difficult to determine experimentally.

125. Emergence of mutational resistance Resistance is a function of the product of original inoculum, rate of reproduction and the mutation rate, divided by the negative growth rate (reduction in susceptibles) If high inoculum size ? resistance If no starting mutants, best S killer ? resistance If starting R mutants, best S killer ? resistance

126. plt Strategies for Restricting the Development of Resistance

127. plt Strategies for Restricting the Development of Resistance Three possible strategies for restricting the development of antimicrobial resistance. To keep concentrations above the MPC To narrow the selection window. To use combination therapy in which pharmacokinetic mismatch is avoided.

128. What is the concentration needed to prevent mutation and/or selection of bacteria with reduced susceptibility? Beta-lactams: we do not know but most likely stay always above the MIC? Aminoglycosides: achieve a peak of 8x the MIC at least Fluoroquinolones: AUC/MIC > 100 h and peak/MIC > 8

130. EMEA "Points to consider" July 2000 Inadequate dosing of antibiotics is probably an important reason for misuse and subsequent risk of resistance A recommendation on proper dosing regimens for different infections would be an important part of comprehensive strategy The possibility to produce such a dose recommendation based on pharmacokinetic and pharmacodynamic considerations will be further investigated in one of the CPMP working parties...

131. Comment d?terminer un sch?ma posologique pour un antibiotique Essais cliniques Dose titration PK/PD

132. Clinical trials

133. Spontaneous cure vs. antibiotic treatment Spontaneous clinical cure Cure with antibiotic treatment

134. Clinical trials Poor diagnostic tools Poor endpoint in clinical trials Poor knowledge about which patients really benefit from antibiotic treatment

135. Les essais cliniques Clinical trials of efficacy are presently almost entirely funded by the pharmaceutical industry and have objectives confined to satisfying regulatory authorities thus, trials which seek to optimize the dose, dose interval and duration of treatment are rarely done

136. Bacteriological vs. clinical success: the Pollyanna phenomenon

137. The Pollyanna phenomenon The clinical efficacy does not always indicate bacteriological efficacy making it difficult to distinguish between antimicrobials on clinical outcomes only or why are statistical differences between 2 antibiotics in clinical outcome rarely seen.

138. L'effet Pollyanna Otite moyenne

139. The Pollyanna phenomenon Otitis media bacteriological cure high (100%) clinical success = 89% other cases = non bacterial aetiology Bacteriological cure low (27%) clinical success = 74% Conclusion : discrimination between "good" and "bad" antimicrobial on clinical outcomes alone would require extremely large clinical trials

140. The Pollyanna phenomenon If efficacy is measured by symptomatic response, drugs with excellent antibacterial activity will appear less efficacious than they really are and drugs with poor antibacterial activity will appear more efficacious than they really are.

141. Essais cliniques Ne sont pas des outils appropri?s pour d?finir un sch?ma posologique Doivent v?rifier (valider) que le sch?ma posologique s?lectionn? par d'autres approches est efficace (essai de confirmation)

142. Les indicateurs PK/PD d'efficacit? Inaptitude des crit?res cliniques ? trouver les bons sch?mas posologiques PK/PD

143. Les indicateurs PK/PD d'efficacit? Principe contr?le l'exposition ? l'antibiotique car la "forme" de l'exposition contr?le l?effet (in vitro) et l'efficacit? (in vivo)

144. La vitesse de bactericidie

148. La bact?ricidie La reconnaissance de deux grands types d'antibiotiques a conduit ? explorer des indicateurs in vivo de l'efficacit? des antibiotiques prenant en compte la concentration et le temps.

149. D'o? viennent les indices PK/PD Mod?les animaux validations cliniques (analyses r?trospectives)

150. In vivo model Murine thigh infection (neutropenic) Pneumoniae in rat

151. Correlation of pharmacodynamic parameters with efficacy Use neutropenic murine thigh-and lung-infection models Evaluate 20-30 different dosing regimens (5 different total doses given at 4-6 different dosing intervals) Measure efficacy from change in Log10 CFU per thigh or lung at the end of 24 h of therapy Correlate efficacy with various pharmacodynamic parameters (time above MIC, peak/MIC, 24h AUC/MIC)

152. Relationship between PK/PD parameters and efficacy for cefotaxime against Klebsiella pneumoniae in a pneumonia model

153. Relationship between 24h AUC/MIC and mortality for Fluoroquinolones against gram negative bacilli in immunocompromised animal models

154. plt Relationship Between T>MIC and Efficacy for Carbapenems (Red), Penicillins (Aqua) and Cephalosporins (Yellow)

155. PK/PD indices as indicator of antibiotic efficacy

156. Quantitative indices of antimicrobial PK/PD Should be mixed (hybrid) indices considering microbiological (MIC) and PK criteria together Able to predict outcome of therapy Able to allow dual individualization (PK and PD) of the dosage regimen

157. Les crit?res PK/PD AUIC (ou AUC/CMI) : quinolones, t?tracyclines Cmax/CMI : aminoglycosides T>CMI : p?nicillines, cephalosporines, macrolides

158. AUIC : definition AUIC = AUC(t1-t2) / MIC Unit = time (h) Established on a 24 h period (in steady state conditions)

159. Pourquoi ces indices sont-ils dits PK et PD AUIC # =

160. Cmax / MIC The inhibitory ratio IR = good predictor of clinical outcome for concentration dependent antibiotic a high Cmax/MIC avoids resistance the "best" index for aminoglycoside

161. T > MIC Time for which drug concentration exceeds MIC T>MIC between t2 - t1 PK determinant : complex clearance, half-life Usually given as a percentage of the dosage interval at steady state

162. The validation of efficacy index clinical data

163. Validation of efficacy index : which is the optimum one in terms of accuracy, reproducibility, clinical relevance in silico simulation in vitro dynamic model animal model clinical trial

164. PK/PD and clinical trials Retrospective analysis clinical ? PK/PD Prospective validation PK/PD ? clinical trials

165. Efficacy index: clinical validation Free serum concentration need to exceed the MIC of the pathogen for 40-50% of the dosing interval to obtain bacteriological cure in 80% of patients

166. Efficacy index: clinical validation

167. AUIC and bacterial eradication

168. AUIC and bacterial resistance Ciprofloxacin AUIC predicts bacterial resistance in nosocomial pneumoniae

169. PK/PD vs. dose-titration trial PK/PD Dose titration Subjects healthy infectious model volunteers patient Endpoints surrogate clinical or correlated bacteriological to clinical cure cure

170. Valeurs ? atteindre pour les indices PK/PD AUIC : 125 h (5 x CMI) Cmax / CMI : 10-12 T>CMI : 50 ? 100%

171. Calcul de la dose (PK/PD) Approche populationnelle PK/PD Dose = x x Clairance (24h)

172. Les indices PK/PD sont bas?s sur des concentrations plasmatiques libres et non tissulaires pourquoi?

173. Where are located the bacteria ECF Most bacteria of clinical interest - respiratory infection - wound infection - digestive tract inf.

174. plt

175. Le site d'infection La plupart des germes pathog?nes sont des parasites extracellulaires Ils se multiplient en dehors des cellules c'est ? dire dans les espaces intercellulaires (substances fondamentales) en contact avec l'eau extracellulaire Ces germes peuvent ?tre phagocyt?s par les PNN et d?truits la phagocytose est la cl? de la gu?rison elle est inhib?e par les facteurs de virulence

176. Le site d'infection (2) Les trois types de bact?ries

177. Intracellular location of bacteria

178. Tissue concentrations According to EMEA "unreliable information is generated from assays of drug concentrations in whole tissues (e.g. homogenates)"

179. En France : la qualit? est privil?gi?e

180. Habitudes d?achats : le poulet surgel? est tr?s peu diffus? en France contrairement ? l?Allemagne

181. Des risques r?els qui n?augmentent pas accompagn?s de nombreux ?v?nements m?diatis?s ?

182. ? conduisant ? de fortes retomb?es sur la consommation

183. Pour les fran?ais, le premier crit?re d??achat reste le go?t

184. Les OGM et les plats pr?par?s : deux produits les plus risqu?s


Other Related Presentations

Copyright © 2014 SlideServe. All rights reserved | Powered By DigitalOfficePro