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1、Latest antibiotic treatment on respiratory tract infections and respiratory tract infection pathogens,Hospital Universitario Ramn y CajalSERVICIO DE MICROBIOLOGA Y PARASITOLOGA,Dr.Rafael Cantn,Antibiotic therapy in community acquired infections:strategies for optimal outcomes and minimized resistanc
2、e emergence,Antibiotic use only in bacterial infections(!)Adequate the antimicrobial treatment strategy to-the etiology-local susceptibility profiles Attempt maximal reduction in bacterial load,with the ultimate aim of bacterial eradication Avoidance of selection processes Antibiotic used based in P
3、K/PD(pharmacokinetic/pharmacodynamic)knowledge,Ball et al.J Antimicrob Chemother 2002;49:31-40,These recommendations are not out of date,November,18th,Antibiotic therapy in community acquired infections:strategies for optimal outcomes and minimized resistance emergence,Antibiotic use only in bacteri
4、al infections(!)Adequate the antimicrobial treatment strategy to-the etiology-local susceptibility profiles Attempt maximal reduction in bacterial load,with the ultimate aim of bacterial eradication Avoidance of selection processes Antibiotic used based in PK/PD(pharmacokinetic/pharmacodynamic)knowl
5、edge,Ball et al.J Antimicrob Chemother 2002;49:31-40,These recommendations are not out of date,Respiratory tract infection pathogens,M.pneumoniaeC.pneumoniaeL.pneumophila,S.pneumoniaeH.influenzaeM.catarrhalisP.aeruginosa,With resistance problems,Without resistance problems,Respiratory tract infectio
6、n pathogens,RTI pathogens:Streptococcus pneumoniae,Europe&North AmericaDecrease penicillin resistance but emergence of very high level resistant clones(Pen 8 mg/L)Maintenance of erythromycin resistance rates but increase of isolates with dual mechanisms mef+erm(B)Low rates of fluoroquinolone resista
7、nce but emergence of specific resistant clones AsiaMaintenance of penicillin resistance(high level resistant clones)Extremely high resistance rates to macrolides,including isolates with dual resistance mechanismLow rates of fluoroquinolone resistance but emergence of specific resistant clones,Cantn
8、et al.Int J Antimicrob Agents.2007;30:546-50Reinert et al.Clin Microbiol Infect 2009;15(Suppl 3):7-11,Streptococcus pneumoniae,2000,2008,Invasive isolates Penicillin resistance(I+R),http:/www.rivm.nl/earss/,S.pneumoniae,Decrease of penicillin(I+R)resistance,http:/www.rivm.nl/earss/,2000 2008I 21.6 1
9、5.7R 11.0 7.1 TOTAL 32.6 22.8,SPAIN,Streptococcus pneumoniae,Local studies(Spain,SAUCE surveillance study,1996-2007),Prez-Trallero et al.Antimicrob Agents Chemother 2005;49:1965-72Sauce 4.Study.GSK.Data on file,RTI pathogens:Streptococcus pneumoniae,Regional trends of penicillin resistance(PROTEKT S
10、tudy),China,Hong Kong,Japan,South Korea and Taiwan,Felmingham,Cantn,Jenkins.J Infec 2007;55:111-8,RTI pathogens:Streptococcus pneumoniae,Regional trends of erythromycin resistance(PROTEKT Study),Felmingham,Cantn,Jenkins.J Infec 2007;55:111-8,RTI pathogens:Streptococcus pneumoniae,Antibacterial susce
11、ptibility prevalence(PROTEKT study)among penicillin-R(PRSP;n=1696)and erythromycin-R(ERSP;n=2638)S.pneumoniae,Felmingham,Cantn,Jenkins.J Infec 2007;55:111-8,Felmingham,Cantn,Jenkins.J Infec 2007;55,111e118,RTI pathogens:Streptococcus pneumoniae,Macrolide resistance mechanisms among erythromycin-R S.
12、pneumoniae isolates collected in selected countries during the PROTEKT study,Dispersion of specific clonal complexes,RTI pathogens:Streptococcus pneumoniae,Resistance profiles in Shanghai(China),High penicillin and erythromycin resistance rates(2004-2005)High rate(42%)of isolates with dual erythromy
13、cin-R genes Absence of fluoroquinolone resistance Population structure:-75%of the isolates belonging to 19F,14,23F,6B and 19A serotypes-dispersion of international resistant clonal complexes:-Taiwan19F-14-Spain23F-1,-Spain6B-2-Taiwan23F-15,Yang et Int J Antimicrob Agenst Chemother 2008;32:386-91,RTI
14、 pathogens:Streptococcus pneumoniae,GLOBAL*Surveillance study,*Global Landscape On the Bactericidal Activity of Levofloxacin,CLSI breakpoints(M100-S17),Local studies(Spain,SAUCE surveillance study,2006-2007),Haemophillus influenzae,RTI pathogens:Haemophillus influenzae,GLOBAL*Surveillance study,*Glo
15、bal Landscape On the Bactericidal Activity of Levofloxacin,CLSI breakpoints(M100-S17):*29.8%-lactamase(+);0.8 amp-R-lactamase(-),RTI pathogens:Pseudomonas aeruginosa,GLOBAL*Surveillance study,*Global Landscape On the Bactericidal Activity of Levofloxacin,CLSI breakpoints(M100-S17),Antibiotic therapy
16、 in community acquired infections:strategies for optimal outcomes and minimized resistance emergence,Antibiotic use only in bacterial infections(!)Adequate the antimicrobial treatment strategy to-the etiology-local susceptibility profiles Attempt maximal reduction in bacterial load,with the ultimate
17、 aim of bacterial eradication Avoidance of selection processes Antibiotic used based in PK/PD(pharmacokinetic/pharmacodynamic)knowledge,Ball et al.J Antimicrob Chemother 2002;49:31-40,These recommendations are not out of date,Bacterial inoculum and RTI,Why is so important the reduction of the bacter
18、ial load or the bacterial erradication for the clinical outcome in RTI?,the acute exacerbation of chronic bronchitis model,Sethi and Murphy.Clin Microbiol Rew 2001;14:336-63Miravitlles.Eur Respir J 2002;20(Suppl 36):9-19Mensa(Suppl 3):42-54,Bacterial inoculum and RTI,Mensa(Suppl 3):42-54,Vicious Cyc
19、le,Bacterial inoculum and RTI,Meta-analysis:12 studies,16 antibioticsR=0.83,Rate of eradication failure,%of clinical failure,Pechre.Infect Med1998;15(Suppl E):4654,Failure in bacterial eradication determines clinical failure in AECB,Acute exacerbation of chronic bronchitis(AECB),Bacterial load,%of p
20、atients,Bacterial load and FEV1 decline in AECB,30 COPD patients with 1 year of lung function follow-up Sputum sampling at the beginning and the end of the study increase in bacterial load(107.47 cfu/ml to 107.93 cfu/ml,p=0.019)decline in pulmonary function(FEV1)(p=0.001),Wilkinson et al.Am J Resp C
21、rit Care Med 2003;167:1090-5,Bacterial inoculum in RTI,Why is so important erradication for the clinical outcome?,antibiotic treatment,Low bacterial load(susceptible),Decrease of bacterial load,Acute exacerbation resolution Decrease of neutrophil inflammation Decrease of bacterial injury,antibiotic
22、treatment,Selection of resistant mutant,High bacterialload(susceptible),natural resistant mutants(10-8),Decline in pulmonary function Recurrent exacerbation status Increase of bacterial injury Increase the risk of resistance Increase of bacterial variation,the bronchitis exacerbation model,Antibioti
23、c therapy in community acquired infections:strategies for optimal outcomes and minimized resistance emergence,Antibiotic use only in bacterial infections(!)Adequate the antimicrobial treatment strategy to-the etiology-local susceptibility profiles Attempt maximal reduction in bacterial load,with the
24、 ultimate aim of bacterial eradication Avoidance of selection processes Antibiotic used based in PK/PD(pharmacokinetic/pharmacodynamic)knowledge,Ball et al.J Antimicrob Chemother 2002;49:31-40,These recommendations are not out of date,Antibiotic resistance:mutational events,A natural resistant popul
25、ation(resistant mutants)is alwayspresent(frequency of mutation)in all bacterial populations The number of resistant mutants increases with the inoculumUnder antibiotic pressure the susceptible subpopulation isinhibited and the resistant mutants can survive and become dominant within the population(s
26、election),The resistant subpopulation may emerge under the action of anantimicrobial agent due to the inhibition of the susceptible population,if the susceptible bacteria()are inhibited by a concentration which is lower than that of necessary to inhibit the resistant subpopulation()a concentration a
27、ble to inhibit both susceptible and resistant populations can be defined,Baquero 28(Suppl 2):S115-27,Mutant prevention concentration and window of selection,Blondeau et al.Antimicrob Agents Chemother 2001;45:433-8,S.pneumoniae,mutant prevention concentration(MPC),Potential for restricting the select
28、ion of resistant mutants moxifloxacin gatifloxacin levofloxacin,%of isolates,%of isolates,%of isolates,This data should be analyzed with pharmacokinetic data,Streptocccus pneumoniae Plasma and intrapulmonary concentrations of levofloxacin,%of isolates,ELF:epithelial lining fluidAM:alveolar macrophag
29、es,Gotfried et al.Chest 2001;119:1114-22,Blondeau et al.Antimicrob Agents Chemother 2001;45:433-8,S.pneumoniae MPC and pharmacokinetics of different fluoroquinolones,MOXIFLOXACIN GATIFLOXACIN LEVOFLOXACIN,Hernsen et al.Antimicrob Agents Chemother 2005;49:1633-35,ELF:epithelial lining fluidAM:alveola
30、r macrophages,Gotfried et al.Chest 2001;119:1114-22,P.aeruginosa mutant prevention concentration(MPC),Garca-Castillo,Morosini,Baquero,Oliver,Baquero,Cantn.15th ECCMID,Prague,2004Hansen et al.Int J Clin Microbiol Infect Dis 2006;27:120-140,P.aeruginosa:fluoroquinolone MPCs and ELF concentrations,Garc
31、a-Castillo,Morosini,Baquero,Oliver,Baquero,Cantn.15th ECCMID,Prague,2004,Epithelial lining fluid concentration(ELF),Gotfried et al.Chest 2001;119:1114-22Boselli et al.Crit Care Med 2005;33:104-9,Antibiotic therapy in community acquired infections:strategies for optimal outcomes and minimized resista
32、nce emergence,Antibiotic use only in bacterial infections(!)Adequate the antimicrobial treatment strategy to-the etiology-local susceptibility profiles Attempt maximal reduction in bacterial load,with the ultimate aim of bacterial eradication Avoidance of selection processes Antibiotic used based in
33、 PK/PD(pharmacokinetic/pharmacodynamic)knowledge,Ball et al.J Antimicrob Chemother 2002;49:31-40,These recommendations are not out of date,Concentration,Time,t1/2,Cmax,tmax,PK/PD parameters of clinical efficacy,AUC:MIC,Metlay et al.Emerg Infect Dis 2006;12:183-190,PK/PD breakpoints:the highest MIC f
34、or which the antimicrobial drug concentrations(at a defined dose)are sufficient to achieve the PK/PD target against a specific organism and for which clinical data support their use,Target(AUC:MIC)attainment values for ciprofloxacin and levofloxacin and different pathogens,Fluoroquinolones,Forrest e
35、t al.Antimicrob Agents Chemother 1993;37:1073-81;Preston et al.JAMA 1998;279:125-9Ambrose et al.Antimicrobial Agents Chemother 2001;45:2793-7Ambrose et al.Infect Dis Clin North Am 2003;17:529-43,Higher doses favors target PK/PD attainment despite MIC increase,AUC:MIC Levofloxacin and S.pneumoniae,Li
36、ster PD.Diagn Microbiol Infect Dis 2002;44:43-9,In vitro pharmacokinetic simulated model,CMI3.22.61.81.4,Susceptibility rates(recent surveillance studiesa)among respiratory pathogens based on PK/PD breakpoints,a:SENTRY,ARISE,Alexander Project,Protekt,Canut et al.J Antimicrob Chemother 2007;60:607-12
37、,AUC:MIC Levofloxacin and P.aeruginosa,Target attainment rates for epithelial lining fluid from humans aftera 750-mg dose of levofloxacin in P.aeruginosa infection,Louie et al.Antimicrobial Agents Chemother 2009;53:332530,Which is the influence of these recommendations on current antimicrobial guide
38、line for RTI infections,Antimicrobial guidelines for RTI:CAP&AECB,Evidence-or consensus-based guidelines1 Adapted to-suspected or demonstrated pathogen-severity of illness and co-moribities-previous antibiotic use2 Often recommend broad-spectrum agents but recent work in antibiotic stewardship promo
39、tes narrow-spectrum agents3,4 Not yet completely updated with recent Pk/Pd knowledge and current resistance trends(should be locally revised),1Blasi et al.Pulm Pharm 24(Suppl 3):iii1-55,Antimicrobial guidelines for RTI,Community acquired pneumonia(British Thoracic Society),Lim et al.Thorax 2009;64(S
40、uppl 3):iii1-55,Antimicrobial guidelines for RTI,Community acquired pneumonia(Japanese Respiratory Society),MaDOI:10.2169/internalmedicine.45.1691,Outpatient Amoxicillin Penicillin+-inhibitorInpatient Penicillin(iv)Cephems(iv),Outpatient Macrolides TetracyclinesInpatient Minocycline(iv)Macrolides,Ou
41、tpatient Amoxicillin High dosesInpatient Penicillin(iv)Cephems(iv)Carbapenems,Adpated to speficic pathogen,Carbapanems(iv)+new quinolone(iv)ormacrolide(iv)Minoclycline(ivi),Antimicrobial guidelines for RTI,Community acquired pneumonia(ATS/IDSA),Mandel et al.Clin Infec Dis 2007;44:S27-72,Antimicrobia
42、l guidelines for RTI,Exacerbation of COPD(GLOD*),Group A:Patients not requiring hospitalization(Stage I-Mild COPD)Group B&C:Patients addmitted to hospital(Stage II-IV:moderate to very severe COPD),Global Initiative for Chronic Obstructive Lung Disease.http:/2005,Variable resistance rates in differen
43、t geographic locations with extremely high levels in some of these areas(i.e.macrolides in S.pneumoniae in Asia,including China)Effective antimicrobial treatments should determine bacterial eradication(CAP)or maximal reduction in bacterial load(AECB)Reduction of resistance development can be achieve
44、d with high doses(surpass MPCs and avoidance of window of selection)Current antimicrobial guidelines should incorporate and be updated with current Pk/Pd knowledge and Pk/Pd breakpoints,Respiratory tract infections:CAP&AECB,Conclusions,Latest antibiotic treatment on respiratory tract infections and
45、respiratory tract infection pathogens,Hospital Universitario Ramn y CajalSERVICIO DE MICROBIOLOGA Y PARASITOLOGA,Dr.Rafael Cantn,Fluoroquinolones,Fluoroquinolones:spectrum of activity,A well-balanced fluroquinolone-antimicrobial activity-pharmacokinetic/pharmacodynamic parameters-adverse effects,Lev
46、ofloxacin,PharmacokineticsAbsorptionDistributionMetabolismExcretion,PharmacodynamicsSpectrum of activityBactericidal activity-Time-dependency-Concentration-dependency,Antibiotic,Clinical efficacy,Resistance avoidance,Antimicrobial use,Yu et al.Antimicrobial Therapy&Vaccines.2005(2nd ed),Pharmacokine
47、tics of fluoroquinolones,Pharmacokinetics of fluoroquinolones,Gotfried et al.Chest 2001;119:1114-1122,Capitano et al.Chest 2004;125:965-73,Healthy adults,Elderly patients,Steady-state concentrations(at 4 h after last dose of 5 days),Gotfried et al.Chest 2001;119:1114-22,Capitano et al.Chest 2004;125
48、:965-73,Healthy adults,Elderly patients,Steady-state concentrations(at 4 h after last dose of 5 days),Pharmacokinetics of fluoroquinolones,Levofloxacin:optimal bioavailability for sequential therapy,Furlanut et al.J Antimicrob Chemother 2003;51:101-6,Pharmacokinetics of fluoroquinolones,1Gotfried et
49、 al.Chest 2001;119:1114-22;2Weinrich et al.IJAA 2006;28:221-5;3 Drusano et al.AAC 2000;2046-51;4Pea et al.PR 2007;55:38-41;5Swoboda et al.JAC 2003;51:459-62;6Rimmele et al.JAC 2004;533-5;7Oberdorfer et al.2004;54:836-9;8Garca-Vzquez et al.EJCMID 2007;26:137-40;9Scotton et al.CID 2001;33:e109-11,Pene
50、tration of levofloxacinin different compartments,Levofloxacin pharmacokinetics,Ratio to serum Macrophages 18.51Liver 3.72Prostate 2.93Sinus 2.54Epithelial lining fluid 1.81Gall bladder 1.85Pleural fluid 1.35Synovial fluid 1.26Diabetic foot 17Bone 16Aqueous humor 0.38CSF 0.39,accumulation of levoflox
