.

, 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