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1、Latest antibiotic treatment on respiratory tract infections and respiratory tract infection pathogens,Hospital Universitario Ramn y Cajal SERVICIO DE MICROBIOLOGA Y PARASITOLOGA,Dr. Rafael Cantn,Antibiotic therapy in community acquired infections: strategies for optimal outcomes and minimized resist
2、ance 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
3、based in PK/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 J Antimicrob Chemother 2002; 49:31-40,These recommendations are not out of date,November, 18th,Antibiotic therapy in community acquired infections: strategies for optimal outcomes and minimized resistance emergence,Antibiotic us
4、e 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 PK/PD (pharmacokine
5、tic/ pharmacodynamic) knowledge,Ball et al. J Antimicrob Chemother 2002; 49:31-40,These recommendations are not out of date,Respiratory tract infection pathogens,M. pneumoniae C. pneumoniae L. pneumophila,S. pneumoniae H. influenzae M. catarrhalis P. aeruginosa,With resistance problems,Without resis
6、tance problems,Respiratory tract infection pathogens,RTI pathogens: Streptococcus pneumoniae,Europe & North America Decrease 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
7、 mef+erm(B) Low rates of fluoroquinolone resistance but emergence of specific resistant clones Asia Maintenance of penicillin resistance (high level resistant clones) Extremely high resistance rates to macrolides, including isolates with dual resistance mechanism Low rates of fluoroquinolone resista
8、nce but emergence of specific resistant clones,Cantn et al. Int J Antimicrob Agents. 2007; 30:546-50 Reinert 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 penici
9、llin (I + R) resistance,http:/www.rivm.nl/earss/,2000 2008 I 21.6 15.7 R 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: 1965-72 Sauce 4. Study. GSK. Data on file,RTI pathoge
10、ns: Streptococcus pneumoniae,Regional trends of penicillin resistance (PROTEKT Study),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, Cant
11、n, Jenkins. J Infec 2007; 55:111-8,RTI pathogens: Streptococcus pneumoniae,Antibacterial susceptibility 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
12、2007; 55, 111e118,RTI pathogens: Streptococcus pneumoniae,Macrolide resistance mechanisms among erythromycin-R S. pneumoniae isolates collected in selected countries during the PROTEKT study,Dispersion of specific clonal complexes,RTI pathogens: Streptococcus pneumoniae,Resistance profiles in Shangh
13、ai (China),High penicillin and erythromycin resistance rates (2004-2005) High rate (42%) of isolates with dual erythromycin-R genes Absence of fluoroquinolone resistance Population structure: - 75% of the isolates belonging to 19F, 14, 23F, 6B and 19A serotypes - dispersion of international resistan
14、t clonal complexes: - Taiwan19F-14 - Spain23F-1, - Spain6B-2 - Taiwan23F-15,Yang et Int J Antimicrob Agenst Chemother 2008; 32:386-91,RTI pathogens: Streptococcus pneumoniae,GLOBAL* Surveillance study,*Global Landscape On the Bactericidal Activity of Levofloxacin,CLSI breakpoints (M100-S17),Local st
15、udies (Spain, SAUCE surveillance study, 2006-2007),Haemophillus influenzae,RTI pathogens: Haemophillus influenzae,GLOBAL* Surveillance study,*Global Landscape On the Bactericidal Activity of Levofloxacin,CLSI breakpoints (M100-S17): *29.8% -lactamase (+); 0.8 amp-R -lactamase (-),RTI pathogens: Pseu
16、domonas aeruginosa,GLOBAL* Surveillance study,*Global Landscape On the Bactericidal Activity of Levofloxacin,CLSI breakpoints (M100-S17),Antibiotic therapy in community acquired infections: strategies for optimal outcomes and minimized resistance emergence,Antibiotic use only in bacterial infections
17、 (!) 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 ) knowled
18、ge,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 bacterial load or the bacterial erradication for the clinical outcome in RTI?, the acute exacerbation of chronic bronchitis model,Sethi a
19、nd Murphy. Clin Microbiol Rew 2001; 14:336-63 Miravitlles. Eur Respir J 2002; 20 (Suppl 36):9-19 Mensa (Suppl 3):42-54,Bacterial inoculum and RTI,Mensa (Suppl 3):42-54,Vicious Cycle,Bacterial inoculum and RTI,Meta-analysis: 12 studies, 16 antibiotics R=0.83,Rate of eradication failure,% of clinical
20、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 patients,Bacterial load and FEV1 decline in AECB,30 COPD patients with 1 year of lung function follow-up Sputum s
21、ampling 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 Crit Care Med 2003; 167:1090-5,Bacterial inoculum in RTI,Why is so important erradication for the clinical
22、outcome?,antibiotic treatment,Low bacterial load (susceptible),Decrease of bacterial load,Acute exacerbation resolution Decrease of neutrophil inflammation Decrease of bacterial injury,antibiotic treatment,Selection of resistant mutant,High bacterial load (susceptible),natural resistant mutants (10-
23、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,Antibiotic therapy in community acquired infections: strategies for optimal outcomes and minimized resistance
24、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
25、 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 population (resistant mutants) is always present (frequency of mutation) in all bacterial p
26、opulations The number of resistant mutants increases with the inoculum Under antibiotic pressure the susceptible subpopulation is inhibited and the resistant mutants can survive and become dominant within the population (selection),The resistant subpopulation may emerge under the action of an antimi
27、crobial 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 able to inhibit both susceptible and resistant populations can be define
28、d,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 selection of resistant mutants moxifloxacin gatifloxacin levofloxacin,%
29、 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 fluid AM: alveolar macrophages,Gotfried et al. Chest 2001; 119:1114-22,Blondeau et al.
30、 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 fluid AM: alveolar macrophages,Gotfried et al. Chest 2001; 119:11
31、14-22,P. aeruginosa mutant prevention concentration (MPC),Garca-Castillo, Morosini, Baquero, Oliver, Baquero, Cantn. 15th ECCMID, Prague, 2004 Hansen et al. Int J Clin Microbiol Infect Dis 2006; 27: 120-140,P. aeruginosa: fluoroquinolone MPCs and ELF concentrations,Garca-Castillo, Morosini, Baquero,
32、 Oliver, Baquero, Cantn. 15th ECCMID, Prague, 2004,Epithelial lining fluid concentration (ELF),Gotfried et al. Chest 2001; 119:1114-22 Boselli et al. Crit Care Med 2005; 33:104-9,Antibiotic therapy in community acquired infections: strategies for optimal outcomes and minimized resistance emergence,A
33、ntibiotic 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 PK/PD (
34、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
35、MIC for 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,
36、Forrest et al. Antimicrob Agents Chemother 1993; 37:1073-81; Preston et al. JAMA 1998; 279:125-9 Ambrose et al. Antimicrobial Agents Chemother 2001; 45:2793-7 Ambrose et al. Infect Dis Clin North Am 2003; 17:529-43,Higher doses favors target PK/PD attainment despite MIC increase,AUC:MIC Levofloxacin
37、 and S. pneumoniae,Lister PD. Diagn Microbiol Infect Dis 2002; 44:43-9,In vitro pharmacokinetic simulated model,CMI 3.2 2.6 1.8 1.4,Susceptibility rates (recent surveillance studiesa) among respiratory pathogens based on PK/PD breakpoints,a: SENTRY, ARISE, Alexander Project, Protekt,Canut et al. J A
38、ntimicrob Chemother 2007; 60:607-12,AUC:MIC Levofloxacin and P. aeruginosa,Target attainment rates for epithelial lining fluid from humans after a 750-mg dose of levofloxacin in P. aeruginosa infection,Louie et al . Antimicrobial Agents Chemother 2009; 53: 332530,Which is the influence of these reco
39、mmendations on current antimicrobial guideline 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 ag
40、ents but recent work in antibiotic stewardship promotes 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 pneumon
41、ia (British Thoracic Society),Lim et al. Thorax 2009; 64 (Suppl 3): iii1-55,Antimicrobial guidelines for RTI,Community acquired pneumonia (Japanese Respiratory Society),MaDOI: 10.2169/internalmedicine.45.1691,Outpatient Amoxicillin Penicillin + -inhibitor Inpatient Penicillin (iv) Cephems (iv),Outpa
42、tient Macrolides Tetracyclines Inpatient Minocycline (iv) Macrolides,Outpatient Amoxicillin High doses Inpatient Penicillin (iv) Cephems (iv) Carbapenems,Adpated to speficic pathogen,Carbapanems (iv) + new quinolone (iv) or macrolide (iv) Minoclycline (ivi),Antimicrobial guidelines for RTI,Community
43、 acquired pneumonia (ATS/IDSA),Mandel et al. Clin Infec Dis 2007; 44:S27-72,Antimicrobial 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
44、 Initiative for Chronic Obstructive Lung Disease. http:/ 2005,Variable resistance rates in different 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 eradic
45、ation (CAP) or maximal reduction in bacterial load (AECB) Reduction of resistance development can be achieved 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,Resp
46、iratory tract infections: CAP & AECB,Conclusions,Latest antibiotic treatment on respiratory tract infections and respiratory tract infection pathogens,Hospital Universitario Ramn y Cajal SERVICIO DE MICROBIOLOGA Y PARASITOLOGA,Dr. Rafael Cantn,Fluoroquinolones,Fluoroquinolones: spectrum of activity,
47、A well-balanced fluroquinolone - antimicrobial activity - pharmacokinetic/ pharmacodynamic parameters - adverse effects,Levofloxacin,Pharmacokinetics Absorption Distribution Metabolism Excretion,Pharmacodynamics Spectrum of activity Bactericidal activity - Time-dependency - Concentration- dependency
48、,Antibiotic,Clinical efficacy,Resistance avoidance,Antimicrobial use,Yu et al. Antimicrobial Therapy & Vaccines. 2005 (2nd ed),Pharmacokinetics 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; 125:965-73,Healthy adults,Elderly patients,Steady-state concentrations (at 4 h after last dose of 5 days),Phar