Streptococcus pneumoniae Haemophilus influenzae β β Key words I β Enterococcus faecium Pseudomonas aeruginosa Streptococcus pneumoniae S. pneumoniae Haemophilus influenzae S. pneumoniae H. influenzae
Table. AntimicrobialactivityofTBPM againststreptococcuspneumoniaewithrecombinantpenicilin-bindingprotein genesfrom penicilin-resistantstrain S.pneumoniae StrainNo. Recipientstrain MSC7007 none pbpgene mutations TBPM 0.00 CDTR 0.0 CFPN 0.05 CTRX 0.0 MIC:μ g/ml AMPC 0.0 FRPM 0.05 MEPM 0.05 <_ 0.05 Isogenicrecombinants MSC700 pbpx 0.00() (6) (6) () 0.06() 0.05() 0.05() 0.0( ) () MSC7009 pbpx,pbpa 0.05() (6) () (6) (6) 0.() 0.() 0.0( ) () MSC700 pbpx,pbpa, (6) () pbpb (6) () (56) () (6) <_ 0.05( ) () Donorstrain MSC70 pbpx,pbpa, (6) (6) pbpb () (6) (56) () () ():themicratioof(isogenicrecombinantsordonorstrain)/recipientstrain, ( ):notcalculated, TBPM,tebipenem;CDTR,cefditoren;CFPN,cefcapene;CTRX,ceftriaxone;AMPC,amoxicilin; FRPM,faropenem;MEPM,meropenem;,clarithromycin;,levofloxacin. > ( ) () S. pneumoniae β H. influenzae S. pneumoniae H. influenzae β II S. pneumoniae H. influenzae S. pneumoniae pbpx pbpa pbpa pbpb β β pbp S. pneumoniae H. influenzae ftsi Enterococcus P. aeruginosa µ
Table. Antimicrobialactivitiesoftebipenem andotheragentsagainstclinicalisolates Strain(strain) Antibacterial agent Range MIC(μ g/ml) MIC50 MIC90 Staphylococcusaureus(MSSA) a) TBPM 0.05 0.0 0.05 0.0 () CDTR CFPN CFDN CTRX MPIPC 0. AMPC > AMPC/CVA 0. FRPM 0. 0. MEPM 0.06 0. IPM 0.05 0.0 0.05 0.0 > > 0.06 TFLX 0.0 0.06 0. Streptococcuspneumoniae(PSSP) b) TBPM 0.00 0.00 0.00 0.00 (5) CDTR 0.00 0. CFPN 0.05 0. CFDN 0.06 CTRX 0.05 PCG 0.05 0.06 0.0 0.06 AMPC 0.05 0. 0.0 0.06 FRPM 0.00 0.0 0.05 0.0 MEPM 0.05 0.0 0.05 0.0 0.05> 0. > TFLX 0. Streptococcuspneumoniae(PISP) b) TBPM 0.00 0. 0.00 0.06 () CDTR 0. CFPN 0. CFDN CTRX PCG 0. AMPC 0. FRPM 0.0 0.06 MEPM 0.0 0.06 0.05> 6 > TFLX 0. Streptococcuspneumoniae(PRSP) b) TBPM 0.0 0. 0.06 0. () CDTR 6 CFPN 6 CFDN > CTRX 6 PCG AMPC FRPM MEPM 0.> > > TFLX 0. (Continued) µ Staphylococcus aureus S. pneumoniae Streptococcus pyogenes Moraxella catarrhalis H. influenzae µ S. pneumoniae pbpa pbpx pbpb µ β
Strain(strain) Table. (Continued) Antibacterial agent Range MIC(μ g/ml) MIC50 MIC90 Moraxelacatarhalis TBPM 0.05 0.06 0.0 0.06 () CDTR 0.0 CFPN 0.06 CFDN 0. CTRX 0.0 6 PCG > 6 > AMPC 6 AMPC/CVA 0.0 FRPM 0.06 MEPM 0.00 0.0 0.00 0.00 0.06 0. 0.0 0. 0.06 0.06 TFLX 0.00 0.0 0.05 0.0 β -lactamase-nonproducing ampicilin-susceptible(blnas) c) Haemophilusinfluenzae (57) β -lactamase-nonproducing ampicilin-resistant(blnar) c) Haemophilusinfluenzae (7) TBPM CDTR CFPN CFDN CTRX ABPC AMPC AMPC/CVA FRPM MEPM AZM TFLX TBPM CDTR CFPN CFDN CTRX ABPC AMPC AMPC/CVA FRPM MEPM AZM TFLX 0.00 0.00 0. 0.00 0. 0.00 0. 0. 0.06 0.05 6 0.05 0.0 0.00 0.0 0. 0.0 0.06 6 6 0.05 6 0. 0.05 0.00 0. 0. 0.05 0.0 0.00 0.06 0.05 0.00 0.0 0.00 0.0 0.06 0.05 0. 0.0 0.05 6 6 6 6 0.0 0.05 (Continued) H. influenzae S. pneumoniae H. influenzae β S. pneumoniae H. influenzae S. pneumoniae H. influenzae β S. pneumoniae µ H. influenzae µ S. pneumoniae H. influenzae
Strain(strain) β -lactamase-producing Haemophilusinfluenzae (0) Table. (Continued) Antibacterial agent TBPM CDTR CFPN CFDN CTRX ABPC AMPC AMPC/CVA FRPM MEPM AZM TFLX Range 0.0 0.00 0.00 0. 6 0.00 > > 0. 6 0.0 0.05 0.06 0.00 0.0 MIC(μ g/ml) MIC50 0. 0.05 0.0 0.00 > > 0.06 0.05 0.00 MIC90 > > 6 6 0.0 0.05 a) MICofMPIPC:<_ μ g/ml b) MICofPCG:PSSP,<_ 0.06 μ g/ml;pisp,0. μ g/ml;prsp,>_ μ g/ml c) MICofABPCagainstβ -lactamase-nonproducingstrain:blnas,<_ μ g/ml;blnar,>_ μ g/ml TBPM,tebipenem;CDTR,cefditoren;CFPN,cefcapene;CFDN,cefdinir;CTRX,ceftriaxone; MPIPC,oxacilin;PCG,penicilin G;ABPC,ampicilin;AMPC,amoxicilin;AMPC/CVA, amoxicilin/clavulanicacid(ratioofconcentration;:,theconcentrationisshownas AMPC);FRPM,faropenem;MEPM,meropenem;IPM,imipenem;,clarithromycin;AZM, azithromycin;,levofloxacin;tflx,tosufloxacin S. pneumoniae H. influenzae β S. pneumoniae H. influenzae β in vitro III PK In vitro µ in vitro in vitro µ
Viable cells ( log CFU/thigh) 0 5 T MIC (R 0.77) 0 0 0 60 0 00 T MIC (%) Viable cells ( log CFU/thigh) C max f/mic (R 0.7 ) 0 5 0.0 0. 0 00 C max f/mic Viable cells ( log CFU/thigh) AUCf/MIC (R 0. ) 0 5 0. 0 00,000 AUCf/MIC Fig.. Relationshipbetweenthreepharmacokinetic-pharmacodynamicparametersandtheviablecelsofStreptococcuspneu moniaeth-0inthighofneutropenicmiceafterhoursoftherapywithtbpm. A:percentageoftimethatplasmaunboundTBPM levelsexceedthemic B:peakofunboundTBPM/MICratio C:-hourAUCofunboundTBPM/MICratio Animals:ICRmice(weeksold,male),n= Pretreatment:intraperitonealinjectionofcyclophosphamide(00mg/kg)daysbeforeinfection Infection:S.pneumoniaeTH-0(MICofTBPM:0.05 μ g/ml)hbeforethestartoftherapy Therapy:subcutaneouslyadministeredwithTBPM ( q:0h, q:0,h, q:0,,6h, q6:0,6,,h) Viablecelcounts:CFU/thighdeterminedhafterthestartoftherapy Eachpoint:themeanfortwothighspermouse Zeroofviablecels:numberofbacteriaatthestartoftherapy(6.logCFU/thigh) R :contributionratio t t
Table. PharmacokineticparametersoforaladministrationofTBPM-PItopediatricpatients Administered dose Age (y.o) cases (Cases) Tmax (hr) Cmax (μ g/ml) t/ (hr) AUC0hr (μ g hr/ml) mg/kg 6mg/kg.±.7.0±. 57 65 0.7±0.6 0.69±0..6±.65 5.0±..0±0.67 0.99±0 5.9±0.9.0±.6 µ µ IV PK-PD S. pneumoniae H. influenzae M. catarrhalis S. pyogenes S. aureus µ µ
Table. Clinicalandbacteriologicaleficacyinadosageandadministrationconfirmationstudyinadults Targetdisease:StudyNo. 50mgt.i.d Treatmentgroup 50mgb.i.d 00mgt.i.d Infectionsinthefieldof Clinicaleficacy 7.%(/).6%(/5) 5.%(9/) otorhinolaryngology Bacteriologicaleficacy 90.7%(9/) 9.%(/5) 9.%(/) Pneumonia Clinicaleficacy Bacteriologicaleficacy 9.%(/6).0%(/5) 90.0%(6/0) 5.0%(7/0) Eficacyrate:Numberofcaseswithefectiveorbeter/Numberofevaluatedcases Eradicationrate:Numberofcasesthatbecamenegative/Numberofevaluatedcases 7.5%(5/0) 9.7%(/9) S. pneumoniae H. influenzae µ µ S. pneumoniae H. influenzae
Table5. Clinicalandbacteriologicaleficacybydiseaseandbytreatmentgroupinaclinicalpediatricstudy Evaluateditem Clinical eficacy Bacteriological eficacy Treatmentgroup mg/kgb.i.d 6mg/kgb.i.d mg/kgb.i.d 6mg/kgb.i.d Otitismedia 9.%(70/75) 96.9%(/) 9.0%(0/07) 00%(6/6) 00%(/) 00%(75/75) Diagnosticnameofinfection Sinusitis 0.%(/6) 0.0%(/0) 0.6%(9/6) 96.%(5/6) 9.7%(/) 9.7%(6/) Eficacyrate= Numberofcaseswithefectiveorbeter/Numberofevaluatedcases Eradicationrate= Numberofstrainsthatbecamenegative/numberofstrains Pneumonia 00%(5/5) 95.%(/) 9.%(5/59) 00%(/) / 00%(6/6) 97.0%(6/6) 9.9%(6/66) 96.5%(/0) 99.5%(9/99) 96.7%(9/0) 99.%(7/9) Causativebacteria S.pneumoniae CLSI PCG H.influenzae Table6. Bacteriologicaleficacybydiseaseinaclinicalpediatricstudy S I R S Otitismedia 00%(0/0) 00%(/) 00%(0/0) 00%(/) 00%(/) Targetdisease Sinusitis 00%(7/7) 5/5 00%(7/7) 5/5 / Pneumonia 5/5 / / / / 00%(0/0) 00%(9/9) 00%(9/9) 00%(/) 00%(/) I / / S R 00%(7/7) 00%(0/0) 00%(5/5) 00%(/).9%(6/) 00%(/) / 00%(9/9) 00%(6/6) 00%(9/9) 9.%(05/07) 00%(6/6) CLSI I 00%(9/9) / / 00%(/) M.catarhalis S.pyogenes S.aureus R 00%(6/6) 00%(9/9) 5/5 / 00%(75/75) / / / 9.7%(6/) / / 00%(6/6) Eradicationrate(Numberofstrainsthatbecamenegative/numberofstrains) S.pneumoniae S:PCGMIC:<_ 0.06,I:PCGMIC:0.,R:PCGMIC:>_ S: MIC:<_,I: MIC:,R: MIC:>_ H.influenzae S:ABPCMIC:<_,I:ABPCMIC:,R:ABPCMIC:>_ 90.9%(0/) 00%(0/0) 00%(9/9) / 99.%(7/9) S. pneumoniae H. influenzae µ
Table7. Clinicaleficacybytreatmentgroupincasesinwhom pretreatmentwasnotefective Targetdisease Treatment group evaluated cases Otitismedia caseswith efectiveor beter Eficacy rate evaluated cases Sinusitis caseswith efectiveor beter Eficacy rate evaluated cases Pneumonia caseswith efectiveor beter Eficacy rate mg/kgb.i.d 6mg/kgb.i.d 7 7 00% 00% 5 / /5 6 6 00% 9.% 00% 9 7 77.% 9 96.6% Table. Clinicaleficacybydiseaseinrecurentcases Targetdisease Treatment group evaluated cases Otitismedia cases withefective orbeter Eficacyrate evaluated cases Sinusitis cases withefective orbeter Eficacyrate mg/kgb.i.d 6mg/kgb.i.d 6 5 9.% 9.7% / / 6 9.9% 5 /5 Severity Table9. Clinicaleficacybytheseverityoftheinfection Treatmentgroup evaluatedcases caseswith efectiveorbeter Eficacyrate mg/kgb.i.d 00% Mild 6mg/kgb.i.d 6 6 00% 9 9 00% mg/kgb.i.d 00% Moderate 6mg/kgb.i.d 7 9.% 0 9 97.5% Table0. Clinicaleficacyinpneumoniapatientsinwhom intravenousantimicrobial therapyisindicated Treatmentgroup mg/kgb.i.d 6mg/kgb.i.d CRP>_ 0mg/dL / / / WBC>_ 0,000/μ L 5/5 / 00%(7/7) CRP>_ 0mg/dLand WBC>_ 0,000/μ L / / Eficacyrate= Numberofcaseswithefectiveorbeter/Numberofevaluatedcases
Table. Clinicalandbacteriologicaleficacybytreatment group in a Phase Iclinicalpediatricstudy (double-blind,comparativestudy) Evaluateditem Clinical eficacy Bacteriological eficacy Treatmentgroup TBPM-PI High-doseCDTR-PI 95%confidence intervalofthe diference TBPM-PI High-doseCDTR-PI 95%confidence intervalofthe diference Eficacyrate/ Eradicationrate 9.%(0/0) 9.6%(7/9) - 0.%.5% 00%(69/69) 9.5%(6/65) -.5%.5% Eficacyrate= Numberofcaseswithefectiveorbeter/ Numberofevaluatedcases Eradicationrate= Numberofstrainsthatbecamenegative/ numberofstrains S. pneumoniae H. influenzae β S. pneumoniae H. influenzae H. influenzae µ µ µ µ
Table. BacteriologicaleficacyoncausativebacteriadetectedinaPhase Iclinicalpediatricstudy(double-blind,comparativestudy) Causativebacteria S.pneumoniae H.influenzae M.catarhalis S.pyogenes S.aureus Treatmentgroup TBPM-PI High-doseCDTR-PI 95%confidence intervalofthe diference TBPM-PI High-doseCDTR-PI 95%confidence intervalofthe diference TBPM-PI High-doseCDTR-PI 95%confidence intervalofthe diference TBPM-PI High-doseCDTR-PI 95%confidence intervalofthe diference TBPM-PI High-doseCDTR-PI 95%confidence intervalofthe diference TBPM-PI High-doseCDTR-PI 95%confidence intervalofthe diference Afterdays administration Eradicationrate 00%(7/7) 6.6%(/) 0.0% 5.% 96.0%(/5) 00%(7/7) -.7%.7% / / - 9.% 00.0% / / 9.%(55/56) 0.%(5/66) 7.7%.% Atcompletion of administration Eradicationrate 00%(/) 96.%(0/) -.0% 9.% 00%(/) 00%(/) 5/5 / / / / 00%(69/69) 9.5%(6/65) -.5%.5% Eradicationrate= Numberofstrainsthatbecamenegative/numberofstrains Table. Evaluationoftheeaseoftakingthedrug Treatmentgroup Veryeasy totake Easytotake Average Hardtotake Toohardto take Rateofeaseof takingthedrug mg/kgb.i.d 6mg/kgb.i.d 0 0 6 5 5 0 0 9.7% 9.7% 5 0 0 9.7% Rateofeaseoftakingthedrug= Veryeasytotake+ Easytotake/ V
Table. RelationbetweenthetargetvalueofPK-PDparameters(AUCf/MIC,Cmax/MICandT> MIC)andthebacteriological eficacyorclinicaleficacyinpediatricpatients PK-PDparameter AUCf/MIC Cmaxf/MIC T> MIC(%) total Eradicationrate (Numberof strains) Bacteriologicaleficacy Persistencerate (Numberof strains) Numberof strains Eficacyrate (Numberof subjects) Clinicaleficacy Poorrate (Numberof subjects) Numberof subjects 6 * 00%() 0%(0) 00%(67) 0%(0) 67 < 6 * 67%() %() 67%() %() 00%() 0%(0) 9%(6) %() 65 < 0%() 0%() 5 00%(5) 0%(0) 5 > 0 0 * :Estimatedtargetvalue 00%() 0%() 99%(5) 0%(0) 0%() %() 5 6 9%(6) 00%(5) 99%(69) %() 0%(0) %() 65 5 70 Table5. Adversedrugreactionsoverview subjectsanalysed caseswithadrs(%) events System OrganClassandPreferedTerm (MedDRA/JV.0.0) Gastrointestinaldisorders Abdominalpain Abdominalpainupper Mushystool Loosebowel Waterystools Discolouredfaeces Stomatitis Vomiting Generaldisordersandadministrationsiteconditions Malaise Pyrexia Thirst Nervoussystem disorders Headache Somnolence Renalandurinarydisorders Chromaturia Dysuria Respiratory,thoracicandmediastinaldisorders Cough Epistaxis Skinandsubcutaneoustissuedisorders Dermatitis Erythema Rash 0 0(.0) 9 events cases(%) 9 9(.) () (0.) (7.5) (7.0) (5.0) (0.) () 5 5(.) (0.7) (0.) (0.) (0.) 6 5(.) (0.7) () () (0.) (0.) () (0.) (0.) (.) (0.) (0.) 6 6(.) Clostridium difficille
Table6. Abnormallaboratorydatachangesoverview subjectsanalysed caseswithadrs(%) events System OrganClassandPreferedTerm (MedDRA/JV.0.0) Alanineaminotransferaseincreased Aspartateaminotransferaseincreased Bloodureaincreased Whitebloodcelcountincreased Plateletcountincreased Eosinophilpercentageincreased Proteinurinepresent (5.) 5 events cases(%) (0.7) (0.7) (0.9) (0.9) 7 7(.6) (0.7) (0.) Table7. TBPM-PI の効能 効果および用法 用量 効能 効果 [ 適応菌種 ] テビペネムに感性の黄色ブドウ球菌, レンサ球菌属, 肺炎球菌, モラクセラ ( ブランハメラ ) カタラーリス, インフルエンザ菌 [ 適応症 ] 肺炎, 中耳炎, 副鼻腔炎 肺炎球菌にはペニシリン耐性肺炎球菌及びマクロライド耐性肺炎球菌を含む インフルエンザ菌にはアンピシリン耐性インフルエンザ菌を含む 効能 効果に関連する使用上の注意カルバペネム系抗生物質の臨床的位置づけを考慮した上で, 本剤の使用に際しては, 他の抗菌薬による治療効果が期待できない症例に限り使用すること 用法 用量通常, 小児にはテビペネムピボキシルとして 回 mg( 力価 )/kg を 日 回食後に経口投与する なお, 必要に応じて 回 6mg( 力価 )/kg まで増量できる 用法 用量に関連する使用上の注意本剤の投与期間は,7 日間以内を目安とすること なお, 本剤の使用にあたっては, 耐性菌の発現等を防ぐため, 原則として感受性を確認し, 疾病の治療上必要な最小限の期間の投与にとどめること β VI S. pneumoniae H. influenzae
Streptococcus pneumoniae Haemophilus influenzae in vitro Streptococcus pneumoniae Haemophilus influenzae Streptococcus pneumoniae
Streptococcus pneumoniae Haemophilus influenzae β β