in vitro Key words Streptococcus pneumoniae β Haemophilus influenzae Escherichia coli I
Table. Antibacteriallevofloxacinactivityagainstclinicalisolates Organism Year Susceptibility(%)(Numberofstrains) MIC(μ g/ml) MSSA.(36) 6.().3(76).(,6)... MRSA 7.3(3).6().(7).3(,6) > > > 6 > 6 MSCNS.(7).().(37) (7) MRCNS 3.3(7).3(3) 6.(6) 3.(,) > Streptococcuspneumoniae ().(3).().(,) Streptococcuspyogenes (7) (33).(36).(676) Enterococcusfaecalis 7.(3) 7.(7) 7.(6) 6.(7) > 6 3 3 Enterococcusfaecium.3().(37).6().3(663) > > 6 6 Haemophilusinfluenzae () ().(67).(,) <_.6 <_.6 <_. <_. Neiseriagonorhoeae.(7).3() 6 6 Moraxela(Branhamela)catarhalis (73) ().(3) (76) <_.6 <_.6.6.6 Escherichiacoli 6.7(363).().(66).(,). Klebsielapneumoniae.(3).().(63).(,). <_.6.. Salmonelaspp. () (6) (6).(3) <_.6 <_.6 <_.6. Proteusmirabilis.(67).6(7).(373).(677) Indole-positiveProteusgroup 3.().(3).(63).3(76) Seratiamarcescens.3(33) 3.() 3.(6) 6.() Citrobacterspp..().(3).6(7).7(7) Enterobacterspp. 6.6() 7.(6) 7.(6) 6.(,) Acinetobacterspp..() 3.(3).7(7).3(3) PseudomonasaeruginosaUTI.() 6.(3) 6.(3) 6.7(3) > 6 6 6 6 PseudomonasaeruginosaRTI.().(6).().(,) in vitro II LVFX Staphylococcus aureus S. pneumoniae Streptococcus pyogenes H. influenzae Moraxella Branhamella catarrhalise. coli Proteus mirabilis E. coli P. mirabilis S. pneumoniae
Table. LevofloxacinpharmacokineticandPK-PDparametersforS.pneumoniaecalculatedbyMonteCarlosimulation Parameter Statistics mg /day Pharmacokinetic Cmax (μ g/ml) AUCh (μ g h/ml) PK-PD Cmax/MIC AUCh/MIC median 6. (thandthpercentiles) (3.3,.) median 6. (thandthpercentiles) (3.6,3.3) median.3 (thandthpercentiles) (.,.) median 7. (thandthpercentiles) (.,37.7) PercentageofsubjectswhosePK-PDparametersreachedthetarget Cmax/MIC>_ (%) 3. AUCh/MIC>_ 3 (%). mg 3/day. (.3,3.). (3.,7.) 3.3 (.6,.) 76. (3.,.) 3.. gyra gyrb parc pare S. pneumoniae S. pneumoniae In vitro S. pneumoniae E. coli E. coli S. pneumoniae E. coli
Log CFU/mL 7 6 3 Time (h) Fig.A. BactericidalactivityoflevofloxacinagainstStrepto coccuspneumoniaeclinicalisolate(eg3)inaninvi tropharmacokineticmodel. Opencircles,mgt.i.d.;closeddiamonds,mgq.d.; solidline,growthcontrol,dotedline;detectionlimit. 7 6 3 6 Time (h) Fig.C. BactericidalactivityoflevofloxacinagainstEscheri chiacoliclinicalisolate(gk)inaninvitropharma cokineticmodel. Opencircles,mgt.i.d.;dotedlinewithasterisks, mgq.d.;closeddiamonds,mgq.d.;solidline,growth control. III Log CFU/mL 7 6 3. 6 3 Levofloxacin ( g/ml) Fig.B. FrequencyofresistantpopulationinStreptococcus pneumoniaeclinicalisolate(eg3)aftersimulating serum concentrationoflevofloxacin. Opencircles,mgt.i.d.;closeddiamonds,mgq.d.; solidline,controlwithnodrugtreatment,dotedline;de tectionlimit. 7 6 3. 6 Levofloxacin ( g/ml) Fig.D. Frequencyofresistantpopulation in Escherichia coliclinicalisolate(gk)aftersimulatingserum con centrationoflevofloxacin. Opencircles,mgt.i.d.;dotedlinewithasterisks, mgq.d.;closeddiamonds,mgq.d.;solidline,control withnodrugtreatment,dotedline;detectionlimit. µ
Table3. Pharmacokineticlevofloxacinparametersin(A)single-doseand(B)multiple-dosestudies (A)Single-dosestudy Dose (mg) n Cmax (μ g/ml) tmax (h) t/ (h) AUCinf (μ g h/ml) CLt/F (L/h) Vdz/F (L) CLr (L/h) 3.7.3..3 7..7...6.6.7 6.6.. Chinese 7.3. 7..7..7...6.....6.76.7..3.. 3.6 36..3.6 7.. 7..7 7 3 3.3.3.. 3.3.6.. 6. 6. 7..,.37.63. 7...3..... 7.. (B)Multiple-dosestudy n Day Cmax (μ g/ml) Ch (μ g/ml) tmax (h) t/ (h) AUCh (μ g h/ml) Vdz/F (L) CLss/F (L/h) CLr (L/h) nonelderly 7 6.. 6.3..37..7.7..... 3.36 3.76.67 6.6 36. 36.37...6.7 7.. elderly 7 6.. 7...7...3 3.3.7.....7. 67..7 3.. 7.6.3..7.6. µ µ µ S. pneumoniae H. influenzae MBcatarrhalis E. coli Enterococcus faecalis Klebsiella pneumoniae Pseudomonas aeruginosa
Table. Pharmacokineticlevofloxacinparametersaftersingleoraladministration(mg)tosubjects withimpairedrenalfunction Group n Cmax (μ g/ml) tmax (h) t/ (h) AUC7h (μ g h/ml) CLt/F (L/h) Vdz/F (L) CLr (L/h) I 7....7 6..3. a).3.7.3....6 I.7.3.. 3. 7.3. b) 7.6 3....6 I.3. 33.7.7.7 7..7 c)..6.3.6..3 Mean± a) GroupI:Ccr>_ ml/min b) GroupI:<_ Ccr< ml/min c) Group I:Ccr< ml/min,exceptfordialysissubjects Table. Clinicaleficacyattreatmentcompletion Diagnosis Respiratorytractinfection Community-acquiredpneumonia Secondaryinfectionofchronic respiratorydiseases Acutebronchitis Urinarytractinfection ComplicatedUTI Pyelonephritis Cystitis UncomplicatedUTI Acuteuncomplicatedcystitis Acuteuncomplicatedpyelonephritis RecurentuncomplicatedUTI Eficacy(%) Chinese 36/3. 77/76 7.3 / 3. 3/37 7. /. 3/ 7. /. 3/7 3. 3/ 6. 3/7 3. 6/ 66.7 / 73.3 /. 37/7 7. 76/6. 7/7.7 /6. S. aureus S. pneumoniae K. pneumoniae H. influenzae Haemophilus parainfluenzae E. coli K. pneumoniae P. mirabilis
Table6. Bacteriologicalresponse Causativebacteria Staphylococcusaureus Staphylococcuscapitis Staphylococcusepidermidis Staphylococcushaemolyticus Staphylococcussaprophyticus CNS Streptococcusagalactiae Streptococcusanginosus Streptococcuspneumoniae Streptococcussalivarius Streptococcussanguinis Streptococcusmitis β -hemolyticstreptococcus Enterococcusfaecalis Enterococcusfaecium Enterococcusavium Enterococcusdurans Enterococcusgalinarum Leuconostocspp. Gemelamorbilorum Neiseriaspp. Moraxela(Branhamela)catarhalis Escherichiacoli Citrobacterfreundi Citrobacterkoseri Klebsielapneumoniae Klebsielaoxytoca Klebsielaozaenae Enterobactercloacae Enterobacteraerogenes Seratiamarcescens Proteusmirabilis Proteusvulgaris Morganelamorgani Providenciaretgeri Providenciaalcalifaciens Pantoeaagglomerans Enterobacteriaceae Haemophilusinfluenzae Haemophilusparainfluenzae Haemophilusspp. Pseudomonasaeruginosa Burkholderiacepacia Stenotrophomonasmaltophilia Acinetobactercalcoaceticus Acinetobacterbaumanni Acinetobacterlwofi Acinetobacterjuni Acinetobacterjohnsoni Eradication(%) respiratorytractinfection urinarytractinfection Chinese Chinese / /(.) /(.) /(.) 3/3 / /(.) / / /(.) /3(.3) / / /(.7) / /(.) /(.) /(6.6) / / / /(.) 7/(7.) /6(6.7) /(.) /(.) /3 /(.) / / / / / /(.) 7/7(.) 7/7(.) /6(3.3) 6/7(6.7) 6/(.) / / / / 6/6(.) 6/6(.) 3/3(.) 3/3(.) / / /(.) /3(33.3) 3/ / / /(.) 3/3(.) / /(.) / 3/3(.) /(.) /6(3.3) / / / / /(.) 37/3(7.) 67/7() /(.) /(6.) /(.) / /(.) / 3/(.) 3/3(.) / /(.) / γ
Table7. Adversedrugreactions PT a) Patientsevaluatedforsafety Patientswithadversedrugreaction(%) 337 3(7.6) Chinese, 367(.) Total, 6(.) Dizziness 6(.) 3(.3) (3.7) Nausea 3(3.) (3.) (3.) Whitebloodcelcountdecreased (.6) (3.) (3.) Insomnia (.6) 3(.) 37(.3) Alanineaminotransferaseincreased 6(.) 3(.) (.) Bloodlactatedehydrogenaseincreased 6(.) 6(.6) Headache (.) (.) 3(.) Diarhoea (.) 7(.6) (.) Vomiting (3.) (.) (.) Aspartateaminotransferaseincreased (.) 7(.) (.) Eosinophilcountincreased (3.6) 7(.6) (.) Plateletcountdecreased (.) (.) Stomachdiscomfort (.) (.) (.) Anorexia (.3) (.) (.) Hepaticfunctionabnormal (.) (.) Plateletcountincreased (.) (.) Rash (.) (.7) 3(.) Neutrophilcountdecreased (.3) (.) 3(.) Asthenia (.) (.) Gamma-glutamyltransferaseincreased (.) (.) (.6) Dyspepsia (.) (.) (.3) Bloodcreatinephosphokinaseincreased (.) a) MedDRA/JV.. Table. Patientprofilesversusadversedrugreactions Patientswithadversedrugreaction(%) Patientprofiles (n= 337) Chinese(n=,) Total(n=,) Gender Male 36/ (.) 6/ (.) 7/7 (7.3) Female 7/6 (36.) 6/7 (.) 63/6 (3) Age < 6 /3 (36.) 3/,7 (.) 37/, (3.6) (yr) 6 to< 7 7/7 (7.) 6/7 (6.) 73/6 (7.) 7 to< /7 (.3) /7 (.3) / (.) / (.) Bodyweight < 3/ (7.3) / 3/ (.) (kg) to< 6 6/ (3.3) 63/7 (.) 3/77 (.) 6 to< / (.) / (3.6) /7 (.) /7 (.3) /76 (.) 3/3 (7.7) Ccr(mL/min) to< /6 (7.) /3 (3.) / (.3) (Cockcroft) to< 3/3 (.) /36 (.) 6/3 (7.) /3 (37.) 7/ (.) /7 (3) unknown /6 (66.7) /6 (66.7)
QTcF Male Female Age<_ Age>_ 6 QTcP QTcB QT n Table. LevofloxacinefectonQT/QTcinterval(ms) Changefrom baseline Levofloxacin.. 3...7.6 7.6 -. Placebo -.3 -. -.. -. -.3 -.6 Meandiference 3..6..3.. 7. -. %CImaximum.. 6..6 7. 6.. -. Diferencebetweenlevofloxacinandplacebotreatmentinchangefrom thebaselineinqt/qtcintervalattmax analyzedusingalinearmixedmodel.themodelincludestreatment,sequence,and periodasfixedefectsandsubjecttorandom efect.thetime-matchedbaselineofqtinterval, age,andgenderareincludedascovariates.qtcp= QT/RR.. IV V
Plasma concentration ( g/ml) Group I (Ccr 7. ml/min) mg qd (A) 7 6 6 Time (h) Plasma concentration ( g/ml) Group II (Ccr 6. ml/min) (B) mg qd Initial dose of mg and subsequent doses of mg qd 7 6 6 Time (h) Plasma concentration ( g/ml) Group III (Ccr.7 ml/min) (C) mg qd Initial dose of mg and subsequent doses of mg qd Initial dose of mg and subsequent doses of mg qod 7 6 6 Time (h) Fig.. Simulatedplasmaconcentrationoflevofloxacinduring7-daytreatment. Plasmaconcentration-timeprofilesfortypicalpatientswithCcr=7.mL/min(GroupI),Ccr=6. ml/min(groupi),andccr=.7ml/min(group I).
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