β β β β β Streptococcus pneumoniaehaemophilus influenzaemoraxella catarrhalismycoplasma pneumoniaechlamydia pneumoniae β Key wordsβ
mys nilc laci ngis Table. Assessmentschedule Parameters Patientcharacteristics potm /s s QOL Bodytemperature Sputum volume Sputum color Cough Bacteriologicalexamination Mycoplasma/ Chlamydiaantibodytiter Viralantigentests Clinicallaboratorytests Adverseevents Atinitiationof studytreatment Acuteexacerbationphase Day Day7 Typicaly,onadailybasis Day :Assessmentbytheinvestigator :Assessmentbythepatient :Donewheneverpossible :Assessedandrecordedinthe TreatmentDiary bythepatientoncedaily Re-treatment Stable phase Relapse phase β I β β β
Mycoplasma pneumoniae Chlamydia pneumoniae Mycoplasma pneumoniaechlamydia pneumoniae M. pneumoniae C. pneumoniae II β β β β β
Patients enrolled: N8 (LVFX: N8, -lactam: N9) Patients evaluated for safety: N8 (LVFX: N96, -lactam: N88) Patients evaluated for efficacy: N9 (LVFX: N9, -lactam: N58) Patients evaluated for QOL: N7 (LVFX: N67, -lactam: N5) Patients excluded from all analyses Patients enrolled outside the study contract period Patients with missing case record cards Patients who used an incorrect antibacterial agent Patients lost to follow-up Patients excluded from efficacy analysis Patients deviating from the eligibility criteria Patients without a Treatment Diary Patients excluded from QOL analysis Patients with missing data for QOL assessment LVFX -lactam Total 5 6 5 5 LVFX -lactam Total 5 5 6 9 8 55 LVFX -lactam Total 8 Fig.. Dispositionofthepatients. β β β β β β β β β β β β β β
Table. Baselinecharacteristicsofthepatients Gender Variables Male Female Total(%) (85.5) 6(.5) LVFX(%) 6(85.) 8(.7) β -lactam (%) 5(86.) 8(.8) < 65 (7.) 7(9.) 6(.) Age >_ 65< 75 95(8.) 75(9.) (.5) >_ 75 (.6) 79(.) (55.) Height Weight Mean±SD Mean±SD 6.6±7. 5.±8.9 6.8±7. 5.±8.5 6.±7.9 5.5±. Outpatient (89.9) 69(88.9) 5(9.) Inpatient/outpatient Inpatient 5(.) (.) (6.9) Unknown No (.) 8(6.) (7.7) Historyofsmoking Yes 9(85.8) 5(8.8) 8 (9.) Unknown 8 6 Smokingindex Severityoftheinfection (accordingtotheinvestigator) Severityoftheinfection (accordingtotheseverity CriteriaoftheJapanese SocietyofChemotherapy) SeverityofCOPD DurationofCOPD(years) Concomitantdrugs Antibacterialmedication within7dayspriortostudy treatment Lowdoselong-term macrolide therapy Concurentdisease Mean±SD Mild Moderate Severe Unknown Mild Moderate Severe Unknown Mild Moderate Severe VerySevere Unknown Mean±SD No Yes No Yes Unknown No Yes Unknown No Yes,57.9±68.9 (58.) 99(9.9) 5(.) 67(.) (67.9) () 6(.6) 8(.7) 96(9.) (6.7) 7.5±5.5 (9.6) 5(9.) (98.8) (.) (85.) 6(.6) 77(.9) 7(69.),76.±689. (5.) 85(.5) (.) 7(8.8) 6(7.) () 8 (.) 6(.8) 7(8.) (8.) 7.±5.6 7(6.8) 7(69.9) 87(98.9) (.) 6(85.) 8(.7) 6(.9) (68.) 997.±6. (7.7) (.6) (.8) (.5) 6(56.5) () 5(8.8) (6.8) (.) 7(.) 8.±5.5 7(.8) 5(.5) 55(98.) (.8) 9(86.) 8(.) 6(7.6) (7.) No 7(7.) (7.9) 7(67.) Homeoxygentherapy Yes 7(9.9) 55(9.) 8 (.7) Unknown 5 No (6.) 99(6.5) (6.) Historyofvaccination Yes 8(8.6) 6(8.5) (8.9) Unknown No (9.5) 7(9.9) 5(89.) Respiratoryphysiotherapy Yes (9.5) 7(9.) 6(.7) Unknown 6 Bodytemperature < 7. >_ 7.< 7.5 >_ 7.5< 9. >_ 9. (7.7) 87(.9) (.6) 7(.8) 8(.7) 65(.) 9(8.) 6(.) 6(7.6) (7.9) 9(.8) (.7) Severe (5.8) 9(7.) (.) Cough Slight 9(5.8) 98(5.) (5.) None 6(.) (.6) (5.) Statistical Test a) Pe=.869 Pe=.8 Pt=.566 Pt=.5 Pe=.599 Pe=. Pt=. Pe=.8 Pe=.78 Pe=.7 Pt=.7 Pe=.56 Pe=.667 Pe=.895 Pe=.67 Pe=.68 Pe=.96 Pe=.798 Pe=.7 Pe=.59 (Continued)
Table. (Continued) Variables Total(%) LVFX(%) β -lactam (%) Statistical Test a) Sputum volume Marked Moderate Slight None (.) 5(6.) 66(6.5). (.) (6.9) 8(5.). 9(5.5) (5.) 8(.). Pe=.699 Sputum color Yelow-green Yelow Lightyelow Whiteorclear (8.) 8(5.) 6(.5) (6.) 7(8.9) (5.9) (.) 7(.) (5.) 5(.) 7(9.) (.) Pe=.69 WBC(/mm ) < 8, >_ 8,<, >_,< 5, >_ 5, Notdetermined 98(6.7) 5(.8) 5(5.) 9(.) 9 75(5.7) 7(.6) 6(8.) 6(.7) 7 (5.) (8.) 7(5.) (6.5) Pe=.5 CRP(mg/dL) <.7 >_.7< 5. >_ 5.< >_ Notdetermined (9.5) 9(56.7) 8(8.) (5.7) 9 8(.) 86(5.) (8.) (8.) 7 (.) (7.7) 8(7.) (6.5) Pe=.657 a) Pe:Fisher sexactprobabilitytest,pt:t-test Efficacy rate (%) 9 8 7 6 5 LVFX group (N9) -lactam group (N58) COX regression analysis: P. 5 6 7 8 9 Fig.. Timecourseoftheeficacyrates. Streptococcus pneumoniaehaemophilus influenzaemoraxella catarrhalis S. pneumoniaeh. influenzaem. catarrhalis S. pneumoniae H. influenzae H. influenzae β Haemophilus influenzae M. catarrhalis S. pneumoniae Mycoplasma pneumoniaechlamydia pneumoniae Mycoplasma pneumoniae
) Sputum volume ) Sputum color 9 LVFX group (N9) -lactam group (N58) 9 LVFX group (N9) -lactam group (N58) 8 8 Improvement rate (%) 7 6 5 Improvement rate (%) 7 6 5 COX regression analysis: P. COX regression analysis: P. 5 6 7 8 9 5 6 7 8 9 ) Cough ) Body temperature 9 8 LVFX group (N88) -lactam group (N55) 9 8 Improvement rate (%) 7 6 5 Improvement rate (%) 7 6 5 LVFX group (N58) -lactam group (N9) COX regression analysis: P. COX regression analysis: P.67 5 6 7 8 9 5 6 7 8 9 Fig.. Time course ofimprovementratesforspecific symptoms (sputum volume,sputum color,cough,and body temperature). Chlamydia pneumoniae β β
) 7.5 ) 7.5 9 9 8 8 7 7 Efficacy rate (%) 6 5 LVFX group (N65) -lactam group (N) Efficacy rate (%) 6 5 LVFX group (N97) -lactam group (N) COX regression analysis: P.96 COX regression analysis: P.676 5 6 7 8 9 5 6 7 8 9 Fig.. Eficacyratesstratifiedbythebaselinebodytemperature. ) Mildmoderate (FEV % pred 5) ) Severeextremely severe (FEV % pred 5%) 9 LVFX group (N8) -lactam group (N6) 9 LVFX group (N6) -lactam group (N) 8 8 7 7 Efficacy rate (%) 6 5 Efficacy rate (%) 6 5 COX regression analysis: P.6 COX regression analysis: P.7 5 6 7 8 9 5 6 7 8 9 Fig.5. EficacyratesstratifiedbytheseverityofCOPD. β III β β
) Time course of QOL ) Improvement of QOL (QOL at each assessment-qol on day ) 9 8 7 6 LVFX group (N67) -lactam group (N5) 5 LVFX group (N67) -lactam group (N5) * * * * * ** ** ** ** VAS 5 VAS Wilcoxon rank-sum test : P.5, : P. Repeated measures ANOVA: P. Wilcoxon rank-sum test : P.5, : P. Repeated measures ANOVA: P. 5 6 7 8 9 5 6 7 8 9 Fig.6. EvaluationofQOL. ) Mildmoderate (FEV % pred 5%) ) Severeextremely severe (FEV % pred 5%) 5 LVFX group (N7) -lactam group (N) 5 LVFX group (N9) -lactam group (N6) VAS VAS Wilcoxon rank-sum test : P.5 Repeated measures ANOVA: P.76 Wilcoxon rank-sum test : P.5, : P. Repeated measures ANOVA: P. 5 6 7 8 9 5 6 7 8 9 Fig.7. ImprovementofQOLstratifiedbytheseverityofCOPD. Table. Readmissionrate No.ofsubjects Group Patientsreadmited(%) Patientsgivenanantibacterialagent atreadmission(%) LVFX 9 (.5) (6.) β -lactam 58 (.) (9.) Reasonforreadmission:Noimprovementofbaselinesymptoms a) Fisher sexactprobabilitytest Statisticaltest a) P=.88 P=.
Percentage of patients with isolated causative bacteria Streptococcus pneumoniae 8.8% (7/8).% (/8) Haemophilus influenzae.% (8/8) Moraxella catarrhalis 5.% (/8) Pseudomonas aeruginosa.% (/8) Haemophilus parainfluenzae 8.8% (7/8) Klebsiella pneumoniae.5% (/8) Other bacteria Gram-positive bacteria Gram-negative bacteria.5% (/8).8% (/8) Fig.8. Isolatedcausativebacteriaandpercentageofpatients. Table. MICsofantibacterialagentsforthecausativebacteria )S.pneumoniae Drug <_.6..5 MIC.5 8 6 6<_ Range MIC5 MIC9 LVFX CFPN-PI CDTR-PI CFDN ABPC CVA/AMPC 5 5 <_.6.5 <_.6.5 <_.6 <_.6 <_.6...5 <_.6 <_.6.5.5 )H.influenzae Drug <_.6..5 MIC.5 8 6 6<_ Range MIC5 MIC9 LVFX CFPN-PI CDTR-PI CFDN ABPC CVA/AMPC 8 5 <_.6 <_.6 <_.6.5.5 6.5 6<_.5 6 <_.6.. 8 <_.6.5 6 6<_ 6 )M.catarhalis Drug <_.6..5 MIC.5 8 6 6<_ Range MIC5 MIC9 LVFX CFPN-PI CDTR-PI CFDN ABPC CVA/AMPC 8 6 <_.6 <_.6 <_.6..5 6 <_.6.5 <_.6.5.5.5. <_.6.5 6.5 β
oitacifissal oitacifissal Table5. Causativebacteriadetectedatthetimeofacuteexacerbationandrecurence No. Group Exacerbation LVFX Streptococcuspneumoniae β -lactam Pseudomonasaeruginosa Moraxelacatarhalis β -lactam Haemophilusinfluenzae Haemophilusinfluenzae LVFX Moraxelacatarhalis Streptococcuspneumoniae 5 LVFX Haemophilusinfluenzae Moraxelacatarhalis 6 LVFX Haemophilusinfluenzae 7 LVFX Haemophilusparainfluenzae Streptococcuspyogenes * ThesamegeneticpaternwasshownbyPFGE. Recurence Streptococcuspneumoniae * Notdetected Moraxelacatarhalis Notdetected Haemophilusparainfluenzae Streptococcuspneumoniae Notdetected Table6. Incidenceofadversedrugreactions Group Patientsevaluatedforsafety Patientswithadversedrugreactions Incidenceofadversedrugreactions Skin n C Gastrointestinal CNS Hepatic Renal Others LVFX 96 7.% Nausea(mild:event) Vomiting(mild:event) Dulheadache(mild:event) Hepaticdysfunction(mild:events) Hepaticdysfunction(moderate:event) Renaldysfunction(mild:event) Epistaxis(mild:event) β -lactam 88.5% Redness/pruritus(mild:event) Diarhea(mild:event) Gastritis(mild:event) Table7. Incidenceofadversedrugreactionsinelderlypatients(>_ 75years) Group Patientsevaluatedforsafety Patientswithadversedrugreactions Incidenceofadversedrugreactions Skin n C Gastrointestinal Hepatic Renal LVFX.5% Hepaticdysfunction (mild:event) Renaldysfunction (mild:event) β -lactam 5.8% Redness/pruritus(mild:event) Gastritis(mild:event) S. pneumoniaeh. influenzaem. catarrhalis β S. pneumoniae H. influenzaem. catarrhalis µ H. influenzae
β β β β S. pneumoniaeh. influenzaem. catarrhalis Mycoplasma pneumoniaechlamydia pneumoniae Chlamydia pneumoniae Mycoplasma pneumoniaechlamydia pneumoniae
Mycoplasma pneumoniae Mycoplasma pneumoniae
Chlamydia pneumoniae Chlamydia pneumoniae Chlamydia pneumoniae Chlamydia pneumoniae Chlamydophila pneumoniae
β β β β β β β β Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Mycoplasma pneumoniae Chlamydia pneumoniae β β