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Φαρμακοδυναμική και πρόληψη ανάπτυξης μικροβιακής αντοχής. ΜΑΡΚΟΣ ΜΑΡΑΓΚΟΣ Επ. Καθηγητής Παθολογίας – Λοιμώξεων Πανεπιστημίου Πατρών. Επιλογή αντιβιοτικού. Υποκείμενη πάθηση, γνώση της λοίμωξης και των πιθανών παθογόνων αιτίων Αποικισμός vs λοίμωξη Γνώση του αντιβιοτικού - PowerPoint PPT Presentation

Transcript of Φαρμακοδυναμική και πρόληψη ανάπτυξης μικροβιακής...

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  • , vs /

  • +MIC

  • ;STOP STOP

  • The spread of antibiotic resistance among respiratory pathogens represents a serious and growing threat to public health. Resistance to penicillins and macrolides is evident in the most common community-acquired bacterial respiratory pathogens, and the prevalence is increasing rapidly. Although resistance to fluoroquinolones is still relatively low, it is likely to spread rapidly as new, extended-spectrum agents become more widely used in the community.

  • > 90% Oxacillin, ceftriaxone, ertapenem, teicoplanin, daptomycin, fucidic acid

    > 70%Cefazolin, rifampicin, tigecycline

    >30%Penicillin G, cefixime, cefotaxime, erythromycin, clarithromycinAzithromycin, moxifloxacin, vancomycin, linezolid, telithromycin

    >10%Amoxicillin, piperacillin, cefpodoxime, cefuroxime, ceftazidimeCiprofloxacin, levofloxacin, medronidazole

  • ; ;

  • ;

  • - , - , DNA / ,

  • , minimal inhibitory concentration. MIC , minimal bactericidal concentration MBC

  • in vitro 105 cfu/ml, - - in vitro,

  • MIC MBC

  • PKPDPK / PD

  • Post-antibiotic effect (PAE)Sub-MIC effectPost-antibiotic sub-MIC effect (PA SME)Post MIC effect (PME)Postantibiotic Leukocyte Enhancement effect (PALE) Post-exposure effectsStandardization of pharmacokinetic/pharmacodynamic terminologyfor anti-infective drugs: an updateMouton et al. JAC 2005; 55:601-607

  • 1-2 1-2 1-2 1-3 3-5 0 0 (1) 1-3 3-8 2-4PAE Gram (+)PAE Gram (-)

  • TimeConcentrationAgent with a long half-lifeAgent with a short half-lifeSelective pressureSelective pressureMIC Baquero. J Chemother 1999

  • , : pH O2 ( ) ( ) (

  • Time kill curvesCFU/mlcontrol

  • ; ; Gram (+). MBC = 2-4 x MICMBC = 8-16 x MIC

  • Gram (+) - - - +/-

    -, , TMP/SMX,

    -,

    - +/- Clinical relevance of bacteriostatic vs. bactericidal mechanisms of actions in the treatment of gram positive infections GA Pankey and LD Sabath CID 2004; 38: 864-70

  • TobramycinCiprofloxacinTicarcillin64 MIC16 MIC4 MIC1 MIC MICCONTROL

  • Cmax : MIC T > MICAUC/MICT>MIC g/mlAUCMICCmax

  • AUC / MIC AUC (MIC)

  • PK/PD

  • T>MIC g/mlAUCMICCmax-

  • > MIC (% )-

  • T > MIC 4 (%) >MIC (%)020204040606080801001000

  • T > MIC S. pneumoniae H. influenzae > MIC (% ) (%)020406080100020406080100Craig, ECCMID 2000 T >MIC 40-50 %

  • -: > C

  • T >MIC -

  • > C90 - PSSP, PISP, PRSP . influenzae

  • T>MIC (% of Dosing Interval)DrugRegimen PSSP PISP PRSP H. fluAmox/Clav 875/125 BID 100 50 32 42Cefaclor500 TID 46 0 0 0Cefuroxime500 BID 73 41 0 35Cefprozil500 BID 78 38 0 18Cefpodoxime200 BID 62 32 0 82Cefixime400 QD 48 0 0 88CeftriaxoneI gm QD 100 78 42 100

    Time Above MIC90 for Oral Beta-Lactams AgainstPSSP, PISP, PRSP, and H. influenzae

  • -MIC 3 mg/LMIC 12 mg/LT > MIC 100%

  • 1 2 g IV 3

  • Lubasch et al. JAC 2003;51: 659-664:

  • Clearance

  • Jaruratanasirikul et al AAC 2005;49(4):1337: >C1 g bolus2 g 3 1 g 3

  • Jaruratanasirikul et al JAC 2005;49(4):13370.5 g 2 1 g 2 0.5 g 1/2

  • Pk/PD

    AUC/MIC 100-125 Gram

    25-35

    Peak/MIC 8-10Gram

  • 107 128 5 32 128 (25%)

  • Thomas et al. AAC 1998; 42:521-527

  • Thomas et al. AAC 1998; 42:521-527

  • : AUC /MIC

  • 43%11.5%1%

    PK/PD 134 , , 500 mg/ 5-14 Preston et al. JAMA 1998; 279:125129

  • - S. pneumoniaeAUC/MIC30-40

  • Ciprofloxacin400/750Levofloxacin500 mgTrovafloxacin200 mgGatifloxacin400 mgMoxifloxacin400 mgAUC : MIC ratio Streptococcus pneumoniae

  • S. pneumoniae 58 gatifloxacin vs levofloxacin

    AUC/MIC < 33.7 64%AUC/MIC >33.7 100%

    Ambrose et al. AAC 2001

  • Pk/PD

    AUC/MIC 100

    Peak/MIC 8-10

  • : Cmax/MIC Moore et al. J Infect Dis 1987; 155:93-99

  • Kashuba et al. AAC 1999; 43:623-629

  • Ambrose et al. CID 2007;44:79

  • PK

  • PK PK 10.000 PK/PD

  • -

  • !

  • :

  • Drlica et al. Rev Med Microbiol 2004; 15: 73-80 (MPC)

  • MIC MPC

  • Nu 118 has a gyrA mutation

  • Neither T>MPC nor Cmax proved to be single correlates for preventing resistancedevelopment. For the two investigated wild-type strains, an AUC/MPC ratio of 22was the single pharmacodynamic index that predicted prevention of resistant mutant development.

  • In vitro hollow fiber infection modelTwo isogenic strains of P. aeruginosa1. wild type2. AmpC stably derepressed mutant [MIC = 1mg/liter]1x 108 CFU/ml - 5

  • OprD MexAB-OprM

  • Jaruratanasirikul et al AAC 2005;49(4):1337: >C1 g bolus2 g 3 1 g 3

  • In vitro kinetic model Streptococcus pneumoniae 90% (MIC = 0.031 mg/liter)9% (MIC = 0.25 mg/liter)1% (MIC = 8 mg/liter)

  • : PK/PD

  • CH NightingaleDEAD BUGS dont mutate

  • ENDANGERED SPECIES