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Latest antibiotic treatment on respiratory tract infections and

Latest antibiotic treatment on respiratory tract infections and respiratory tract infection pathogens. Dr. Rafael Cantón. Hospital Universitario Ramón y Cajal SERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA. Antibiotic therapy in community acquired infections:

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Latest antibiotic treatment on respiratory tract infections and

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  1. Latest antibiotic treatment on respiratory tract infections and respiratory tract infection pathogens Dr. Rafael Cantón Hospital Universitario Ramón y CajalSERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA

  2. Antibiotic therapy in community acquired infections: strategies for optimal outcomes and minimized resistance emergence Ball et al. J Antimicrob Chemother 2002; 49:31-40 • Antibiotic use only in bacterial infections (!) • Adequate the antimicrobial treatment strategy to • - the etiology • - local susceptibility profiles • Attempt maximal reductionin bacterial load, with the ultimate • aim of bacterial eradication • Avoidance of selection processes • Antibiotic used based in PK/PD (pharmacokinetic/ • pharmacodynamic) knowledge These recommendations are not out of date…

  3. November, 18th

  4. Antibiotic therapy in community acquired infections: strategies for optimal outcomes and minimized resistance emergence Ball et al. J Antimicrob Chemother 2002; 49:31-40 • Antibiotic use only in bacterial infections (!) • Adequate the antimicrobial treatment strategy to • - the etiology • - local susceptibility profiles • Attempt maximal reductionin bacterial load, with the ultimate • aim of bacterial eradication • Avoidance of selection processes • Antibiotic used based in PK/PD (pharmacokinetic/ • pharmacodynamic) knowledge These recommendations are not out of date…

  5. Respiratory tract infection pathogens

  6. M. pneumoniae C. pneumoniae L. pneumophila S. pneumoniae H. influenzae M. catarrhalis P. aeruginosa Respiratory tract infection pathogens With resistance problems Without resistance problems

  7. 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 [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 resistance but emergence of • specific resistant clones Cantón et al. Int J Antimicrob Agents. 2007; 30:546-50 Reinert et al. Clin Microbiol Infect 2009; 15 (Suppl 3):7-11

  8. Streptococcus pneumoniae Invasive isolates Penicillin resistance (I+R) 2000 2008 http://www.rivm.nl/earss/

  9. S. pneumoniae Decrease of penicillin (I + R) resistance 2000 2008 I 21.6 15.7 R 11.0 7.1 TOTAL 32.6 22.8 SPAIN http://www.rivm.nl/earss/

  10. Australian = 657 Far Eastn = 5155 LatinAmerica n = 2889 NorthAmerican = 4155 NorthernEuropen = 7170 SouthernEuropen = 5479 South Africa n = 1611 RTI pathogens: Streptococcus pneumoniae • Regional trends of penicillin resistance (PROTEKT Study) China, Hong Kong, Japan, South Korea and Taiwan Felmingham, Cantón, Jenkins. J Infec 2007; 55:111-8

  11. RTI pathogens: Streptococcus pneumoniae • Regional trends of erythromycin resistance (PROTEKT Study) China, Hong Kong, Japan, South Korea and Taiwan Prevalence of resistance (%) Australian = 657 Far Eastn = 5155 LatinAmerican = 2889 NorthAmerican = 4155 NorthernEuropen = 7170 SouthernEuropen = 5479 South Africa n = 1611 Felmingham, Cantón, Jenkins. J Infec 2007; 55:111-8

  12. RTI pathogens: Streptococcus pneumoniae Antibacterial susceptibility prevalence (PROTEKT study) among penicillin-R(PRSP; n=1696) and erythromycin-R (ERSP; n=2638) S. pneumoniae Felmingham, Cantón, Jenkins. J Infec 2007; 55:111-8

  13. RTI pathogens: Streptococcus pneumoniae • Macrolide resistance mechanisms among erythromycin-R S. pneumoniae isolates collected in selected countries during the PROTEKT study Felmingham, Cantón, Jenkins. J Infec 2007; 55, 111e118 Dispersion of specific clonal complexes

  14. RTI pathogens: Streptococcus pneumoniae • Resistance profiles in Shanghai (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 • resistant clonal complexes: • - Taiwan19F-14 - Spain23F-1, • - Spain6B-2 - Taiwan23F-15 Yang et Int J Antimicrob Agenst Chemother 2008; 32:386-91

  15. RTI pathogens: Streptococcus pneumoniae • GLOBAL* Surveillance study CLSI breakpoints (M100-S17) *Global Landscape On the Bactericidal Activity of Levofloxacin

  16. RTI pathogens: Haemophillus influenzae • GLOBAL* Surveillance study CLSI breakpoints (M100-S17): **29.8% β-lactamase (+); 0.8 amp-R β-lactamase (-) *Global Landscape On the Bactericidal Activity of Levofloxacin

  17. RTI pathogens: Pseudomonas aeruginosa • GLOBAL* Surveillance study CLSI breakpoints (M100-S17) *Global Landscape On the Bactericidal Activity of Levofloxacin

  18. Antibiotic therapy in community acquired infections: strategies for optimal outcomes and minimized resistance emergence Ball et al. J Antimicrob Chemother 2002; 49:31-40 • Antibiotic use only in bacterial infections (!) • Adequate the antimicrobial treatment strategy to • - the etiology • - local susceptibility profiles • Attempt maximal reductionin bacterial load, with the ultimate • aim of bacterial eradication • Avoidance of selection processes • Antibiotic used based in PK/PD (pharmacokinetic/ • pharmacodynamic ) knowledge These recommendations are not out of date…

  19. 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 and Murphy. Clin Microbiol Rew 2001; 14:336-63 Miravitlles. Eur Respir J 2002; 20 (Suppl 36):9-19 Mensa & Trilla Clin Microbiol Infect 2006; (Suppl 3):42-54

  20. Bacterial inoculum and RTI Vicious Cycle Mensa & Trilla Clin Microbiol Infect 2006; (Suppl 3):42-54

  21. Bacterial inoculum and RTI • Failure in bacterial eradication determines clinical failure in AECB Meta-analysis: 12 studies, 16 antibiotics R=0.83 % of clinicalfailure Rate of eradicationfailure Pechère. Infect Med1998;15 (Suppl E): 46–54

  22. 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 Crit Care Med 2003; 167:1090-5

  23. Bacterial inoculum in RTI • Why is so important erradication for the clinical outcome? the bronchitis exacerbation model Acute exacerbation resolution Decrease of neutrophil inflammation Decrease of bacterial injury antibiotic treatment Decrease of bacterial load Low bacterial load (susceptible) Decline in pulmonary function Recurrent exacerbation status Increase of bacterial injury Increase the risk of resistance Increase of bacterial variation natural resistant mutants (10-8) antibiotic treatment High bacterial load (susceptible) Selection of resistant mutant

  24. Antibiotic therapy in community acquired infections: strategies for optimal outcomes and minimized resistance emergence Ball et al. J Antimicrob Chemother 2002; 49:31-40 • Antibiotic use only in bacterial infections (!) • Adequate the antimicrobial treatment strategy to • - the etiology • - local susceptibility profiles • Attempt maximal reductionin bacterial load, with the ultimate • aim of bacterial eradication • Avoidance of selection processes • Antibiotic used based in PK/PD (pharmacokinetic/ • pharmacodynamic ) knowledge Surpass the MPCs These recommendations are not out of date…

  25. Antibiotic resistance: mutational events • A natural resistant population (resistant mutants) is always • present (frequency of mutation) in all bacterial populations • 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) bacterial inoculum susceptible bacteria resistant bacteria

  26. antibiotic The resistant subpopulation may emerge under the action of an antimicrobial agent due to the inhibition of the susceptible population

  27. 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 defined • MPC (mutant prevention concentration) • a concentration which is able to inhibit the resistant subpopulation • … and also can inhibit the susceptible population • concentration that prevents the emergence of resistance mutants • MIC of the resistant population window of selection?

  28. Mutant prevention concentration and window of selection • Baquero & Negri. BioEssays 1997; 19: 731-6 • Drlica K. ASM News 2001; 67:27-33 • Cantón et al. Inter J Antimicrob Chemother 2006; 28 (Suppl 2):S115-27

  29. S. pneumoniae, mutant prevention concentration (MPC) • Potential for restricting the selection of resistant mutants moxifloxacin > gatifloxacin > levofloxacin % of isolates % of isolates % of isolates Blondeau et al. Antimicrob Agents Chemother 2001; 45:433-8 This data should be analyzed with pharmacokinetic data

  30. 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. Antimicrob Agents Chemother 2001; 45:433-8

  31. S. pneumoniae – MPC and pharmacokinetics of different fluoroquinolones MOXIFLOXACIN GATIFLOXACIN LEVOFLOXACIN ELF: epithelial lining fluid AM: alveolar macrophages Gotfried et al. Chest 2001; 119:1114-22 Hernsen et al. Antimicrob Agents Chemother 2005; 49:1633-35

  32. P. aeruginosa – mutant prevention concentration (MPC) García-Castillo, Morosini, Baquero, Oliver, Baquero, Cantón. 15th ECCMID, Prague, 2004 Hansen et al. Int J Clin Microbiol Infect Dis 2006; 27: 120-140

  33. 1000 LEVOFLOXACIN 100 22.1 µg/ml (750 mg/24h) 17.8 µg/ml (500 mg/12h) 10 9.9 µg/ml (500 mg/24h) µg/ml 1 0.1 0.01 MPC 1000 CIPROFLOXACIN MIC 100 10 µg/ml 2.3 µg/ml (750 mg/24h) 1.8 µg/ml (500 mg/12h) 1 0.1 0.01 strains P. aeruginosa: fluoroquinolone MPCs and ELF concentrations Epithelial lining fluid concentration (ELF) Gotfried et al. Chest 2001; 119:1114-22 Boselli et al. Crit Care Med 2005; 33:104-9 García-Castillo, Morosini, Baquero, Oliver, Baquero, Cantón. 15th ECCMID, Prague, 2004

  34. Antibiotic therapy in community acquired infections: strategies for optimal outcomes and minimized resistance emergence Ball et al. J Antimicrob Chemother 2002; 49:31-40 • Antibiotic use only in bacterial infections (!) • Adequate the antimicrobial treatment strategy to • - the etiology • - local susceptibility profiles • Attempt maximal reductionin bacterial load, with the ultimate • aim of bacterial eradication • Avoidance of selection processes • Antibiotic used based in PK/PD (pharmacokinetic/ • pharmacodynamic ) knowledge These recommendations are not out of date…

  35. Aminoglycosides Fluoroquinolones Cmax : MIC Tetracyclines Glicopeptides Fluoroquinolones MIC Beta-lactams Macrolides Linezolid Texposition PK / PD parameters of clinicalefficacy Cmax AUC : MIC t1/2 Concentration tmax Time

  36. PK/PD breakpoints: • the highest 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 Metlay et al. Emerg Infect Dis 2006; 12:183-190

  37. Fluoroquinolones • Target (AUC:MIC) attainment values for ciprofloxacin and • levofloxacin and different pathogens 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

  38. AUC:MIC Levofloxacin and S. pneumoniae CMI 3.2 2.6 1.81.4 In vitro pharmacokinetic simulated model Lister PD. Diagn Microbiol Infect Dis 2002; 44:43-9

  39. 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

  40. Which is the influence of these recommendations • on current antimicrobial guideline for RTI infections

  41. 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 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 & Therap 2006; 361-9 2Mandel et al. Clin Infec Dis 2007; 44:S27-72 3Dryden et al. J Antimicrob Chemoter 2009; 64:1123-5 4Lim et al. Thorax 2009; 24 (Suppl 3):iii1-55

  42. Antimicrobial guidelines for RTI • Community acquired pneumonia (British Thoracic Society) Lim et al. Thorax 2009; 64 (Suppl 3): iii1-55

  43. Antimicrobial guidelines for RTI • Community acquired pneumonia (Japanese Respiratory Society) Outpatient Amoxicillin High doses Inpatient Penicillin (iv) Cephems (iv) Carbapenems Outpatient Macrolides Tetracyclines Inpatient Minocycline (iv) Macrolides Outpatient Amoxicillin Penicillin + β-inhibitor Inpatient Penicillin (iv) Cephems (iv) Adpated to speficic pathogen Carbapanems (iv) + new quinolone (iv) or macrolide (iv) Minoclycline (ivi) MaDOI: 10.2169/internalmedicine.45.1691

  44. Antimicrobial guidelines for RTI • Community acquired pneumonia (ATS/IDSA) Mandel et al. Clin Infec Dis 2007; 44:S27-72

  45. 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 Initiative for Chronic Obstructive Lung Disease. http://www.goldcopd.com/ 2005

  46. Respiratory tract infections: CAP & AECB • Conclusions • 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 eradication (CAP) or maximal reductionin 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

  47. Latest antibiotic treatment on respiratory tract infections and respiratory tract infection pathogens Dr. Rafael Cantón Hospital Universitario Ramón y CajalSERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA

  48. Fluoroquinolones

  49. Fluoroquinolones: spectrum of activity

  50. quinolonic ring ciprofloxacin levofloxacin moxifloxacin garenoxacin

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