日本化学療法学会雑誌第57巻第1号

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1 In vitro Streptococcus pneumoniae Escherichia coli in vitro Streptococcus pneumoniae Escherichia coli µs. pneumoniae E. coli µ Key words in vitrostreptococcus pneumoniae Escherichia coli Escherichia coli Streptococcus pneumoniae Haemophilus influenzae S. pneumoniae In vitro

2 Concentration of levofloxacin ( g/ml) Fig.. Simulatedbloodconcentrationoflevofloxacininanin vitropharmacokineticmodel. Opencircles,00mgt.i.d.;closeddiamonds,00mgq.d.; dotedlinewithasterisks,0mgq.d.;dotedlinewith closedtriangles,0mgb.i.d. in vitro I S. pneumoniae µ E. coli β β In vitro S. pneumoniae E. coli S. pneumoniae E.coli S. pneumoniae

3 S. pneumoniae E. coli S. pneumoniae gyra gyrb parc pare S. pneumoniae gyra gyrb parc pare E. coli gyra gyrb parc pare S. pneumoniae µ E. coli β µ II In vitro S. pneumoniae S. pneumoniae µ S. pneumoniae

4 (A) (C) (B) (D) (E) (F) (G) Fig.. BactericidalactivityoflevofloxacinagainstclinicalisolatesofStreptococcuspneumoniaeinaninvitro pharmacokineticmodel. (A)S.pneumoniaeEG00,(B)S.pneumoniaeEG000,(C)S.pneumoniaeEG00,(D)S.pneumoniae EG00,(E)S.pneumoniaeEG00,(F)S.pneumoniaeEG00,(G)S.pneumoniaeEG00.Opencircles, 00mgt.i.d.;closeddiamonds,00mgq.d.;solidline,growthcontrol,dotedline;detectionlimit. µ

5 S. pneumoniae E. coli (A) Levofloxacin ( g/ml) (C) Levofloxacin ( g/ml) (B) Levofloxacin ( g/ml) (D) Levofloxacin ( g/ml) (E) Levofloxacin ( g/ml) (F) Levofloxacin ( g/ml) (G) Levofloxacin ( g/ml) Fig.. FrequencyofresistantpopulationinclinicalisolatesofStreptococcuspneumoniaeaftersimulating bloodconcentrationoflevofloxacin. (A)S.pneumoniaeEG00,(B)S.pneumoniaeEG000,(C)S.pneumoniaeEG00,(D)S.pneumoniae EG00,(E)S.pneumoniaeEG00,(F)S.pneumoniaeEG00,(G)S.pneumoniaeEG00.Opencir cles,00mgt.i.d.;closeddiamonds,00mgq.d.;solidline,controlwithnodrugtreatment,dotedline; detectionlimit. S. pneumoniae µ µ µ

6 Table. Pharmacokinetic/pharmacodynamicparametersandbactericidalefectoflevofloxacinin00mgt.i.d.and00mgq.d.models instreptococcuspneumoniae StrainNo. DetailedMIC a (μ g/ml) Simulation model AUC/MIC Cmax/MIC LogofCFU/mL at0h LogofCFU/mL ath Degreein population analysis b EG00 EG000 EG00 EG00 EG00 EG00 EG mgt.i.d. 00mgq.d. 00mgt.i.d. 00mgq.d. 00mgt.i.d. 00mgq.d. 00mgt.i.d. 00mgq.d. 00mgt.i.d. 00mgq.d. 00mgt.i.d. 00mgq.d. 00mgt.i.d. 00mgq.d a :MICwastestedtimesandtheaveragecalculated. b :Degreeofthesusceptibilityreductiontolevofloxacinath. S. pneumoniae E. coli E. coli E. coli µ E. coli µ µ µ E. coli µ E. coli E. coli E. coli

7 S. pneumoniae E. coli (A) (C) (B) (D) (E) Fig.. BactericidalactivityoflevofloxacinagainstclinicalisolatesofEscherichiacoliinaninvitropharmacoki neticmodel. (A)E.coliGK000,(B)E.coliGK00,(C)E.coliGK000,(D)E.coliGK00,(E)E.coliGK00.Open circles,00mgt.i.d.;dotedlinewithasterisks,0mgq.d.;dotedlinewithclosedtriangles,0mgb.i.d.; closeddiamonds,00mgq.d.;solidline,growthcontrol. E. coli S. pneumoniae S. pneumoniae

8 (A) (B) LVFX ( g/ml) LVFX ( g/ml) (C) LVFX ( g/ml) (D) LVFX ( g/ml) (E) LVFX ( g/ml) Fig.. FrequencyofresistantpopulationinclinicalisolatesofEscherichiacoliaftersimulatingbloodconcen trationoflevofloxacin. (A)E.coliGK000,(B)E.coliGK00,(C)E.coliGK000,(D)E.coliGK00,(E)E.coliGK00.Open circles,00mgt.i.d.;dotedlinewithasterisks,0mgq.d.;dotedlinewithclosedtriangles,0mgb.i.d.; closeddiamonds,00mgq.d.;solidline,controlwithnodrugtreatment,dotedline;detectionlimit. S. pneumoniae S. pneumoniae S. pneumoniae S. pneumoniae S. pneumoniae

9 S. pneumoniae E. coli Table. Pharmacokinetic/pharmacodynamicparametersandbactericidalefectoflevofloxacinin00mgt.i.d.,0mgq.d.,0mg b.i.d.,and00mgq.d.modelsinescherichiacoli StrainNo. DetailedMIC a (μ g/ml) Simulation model AUC/MIC Cmax/MIC LogofCFU/mL at0h LogofCFU/mL ath Degreein population analysis b GK mgt.i.d. 0mgq.d. 00mgq.d GK mgt.i.d. 0mgq.d. 00mgq.d GK mgt.i.d. 0mgq.d. 0mgb.i.d. 00mgq.d GK mgt.i.d. 0mgq.d. 0mgb.i.d. 00mgq.d GK00. 00mgt.i.d. 0mgq.d. 0mgb.i.d. 00mgq.d a :MICwastestedtimesandtheaveragewascalculated. b :Degreeofthesusceptibilityreductiontolevofloxacinath. Table. MICswithorwithoutreserpineandaminoacidsubstitutionsintheQRDRaftertreatmentwithlevofloxacin00mgt.i.d. model Isolate EG000 ParC Aminoacidsubstitution ParE GyrA Levofloxacin MIC(μ g/ml) Alone Ciprofloxacin + Reserpine LVFX/EG000- a Ser Tyr LVFX/EG000- Asp Asn EG00 LVFX/EG00- LVFX/EG00- LVFX/EG00- EG00 LVFX/EG00- LVFX/EG00- LVFX/EG00- EG00 LVFX/EG00- LVFX/EG00- EG00 LVFX/EG00- LVFX/EG00- Asp Asn Ser Tyr Asp Tyr Asp Tyr Asp Asn Ser Phe Asp Asn Ser Phe a :LVFX,isolateaftertreatmentwithlevofloxacin00mgt.i.d.model. b :Valueslistedarereduction(n-fold)inMICofciprofloxacinwithadditionofreserpine(0μ g/ml) Ratio b E. coli E. coli

10 Table. MICswithorwithoutPAβ NandaminoacidsubstitutionsintheQRDRaftertreatmentwith levofloxacin00mgt.i.d.modelor0mgq.d.model Isolate GK00 LVFX/GK00 GK000 LVFX/GK000- LVFX/GK000- GK00 LVFX/GK00- LVFX/GK00- GK00 LVFX/GK00 LVFX simulation model a 00mgt.i.d. 00mgt.i.d. 0mgq.d. 00mgt.i.d. 0mgq.d. 0mgq.d. Aminoacidsubstitution GyrA Ser Leu Ser Leu Ser Leu Ser Leu Asp Gly Ser Leu Asp Gly Ser Leu Ser Leu Ser Leu Ser Leu Ser Leu ParC Glu Gly Glu Gly Ser0 Ile Ser0 Ile Ser0 Ile MIC(μ g/ml) Levofloxacin Alone + PAβ N Ratio b a :Notreatment, b :Valueslistedarereduction(n-fold)inMICoflevofloxacinwithadditionofPhe-Arg-β - naphthylamide(paβ N,00μ g/ml). E. coli E. coli E. coli E. coli β β E. coli E. coli III in vitro in vitro S. pneumoniae E. coli S. pneumoniae S. pneumoniae in vitro S. pneumoniae E. coli S. pneumoniae E. coli S. pneumoniae E. coli

11 S. pneumoniae E. coli in vitro Pseudomonas aeruginosa P. aeruginosa E. coli S. pneumoniae S. pneumoniae in vitro S. pneumoniae in vitro E. coli E. coli in vitro E. coli S. pneumoniae S. pneumoniae µ µ S. pneumoniae µ S. pneumoniae µ S. pneumoniae in vitro

12 Streptococcus pneumoniae Streptococcus pneumoniae In vitro Streptococcus pneumoniae Streptococcus pneumoniae Streptococcus pneumoniae Streptococcus pneumoniae Pseudomonas aeruginosa Pseudomonas aeruginosa Streptococcus pneumoniae Streptococcus pneumoniae Streptococcus pneumoniae Streptococcus pneumoniae Escherichia coli

13 S. pneumoniae E. coli in vitro Escherichia coli Streptococcus pneumoniae Streptococcus pneumoniae Streptococcus pneumoniae gyra gyrb parc pare Streptococcus pneumoniae Streptococcus pneumoniae Streptococcus pneumoniae Streptococcus pneumoniae Streptococcus pneumoniae Streptococcus pneumoniae Streptococcus pneumoniae

14 Streptococcus pneumoniae Escherichia coli in vitro Streptococcus pneumoniae Escherichia coli in vitro µ S. pneumoniae E. coli µ

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