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

2. Antibiotic 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 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 J Antimicrob Chemother 2002; 49:31-40 These recommendations are not out of date…

3. November, 18 th

4. Antibiotic 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 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 J Antimicrob Chemother 2002; 49:31-40 These recommendations are not out of date…

5. Respiratory tract infection pathogens Micro-organisms Acute Pneumonia Pathogenic colonization Exacerbation (COPD) Bronchiectasis Haemophilus influenzae +++++ Streptococcus pneumoniae +++++++++ Staphylococcus aureus  ++ Pseudomonas aeruginosa  +++ Other NFGNB  Mycoplasma pneumoniae +++  Chlamydophila pneumoniae ++  Legionella pneumophila  ++ Viruses ++

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

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

9. S. pneumoniae Decrease of penicillin (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

10. Streptococcus pneumoniae  Local studies (Spain, SAUCE surveillance study, 1996-2007) Pérez-Trallero et al. Antimicrob Agents Chemother 2005; 49: 1965-72 Sauce 4. Study. GSK. Data on file

11. Australia n = 657 Far East n = 5155 Latin America n = 2889 North America n = 4155 Northern Europe n = 7170 Southern Europe n = 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

12. RTI pathogens: Streptococcus pneumoniae  Regional trends of erythromycin resistance (PROTEKT Study) Felmingham, Cantón, Jenkins. J Infec 2007; 55:111-8 Australia n = 657 Far East n = 5155 Latin America n = 2889 North America n = 4155 Northern Europe n = 7170 Southern Europe n = 5479 South Africa n = 1611 China, Hong Kong, Japan, South Korea and Taiwan Prevalence of resistance (%)

13. 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

14. Felmingham, Cantón, Jenkins. J Infec 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

15. 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

16. RTI pathogens: Streptococcus pneumoniae GLOBAL* Surveillance study *Global Landscape On the Bactericidal Activity of Levofloxacin Agent Asia (n=564) China (n=105) MIC 90 (mg/L)S (%)MIC 90 (mg/L)S (%) Penicillin440.1453.3 Amox-clavulanate>480.9>484.8 Cefuroxime-axetil>446.5>462.9 Ceftriaxone274.1281.0 Azithromycin>422.5>410.5 Levofloxacin198.0199.0 Trimeth-sulfa>438.3>426.7 CLSI breakpoints (M100-S17)

17. Local studies (Spain, SAUCE surveillance study, 2006-2007) Haemophillus influenzae

18. RTI pathogens: Haemophillus influenzae GLOBAL* Surveillance study *Global Landscape On the Bactericidal Activity of Levofloxacin CLSI breakpoints (M100-S17): **29.8% β-lactamase (+); 0.8 amp-R β-lactamase (-) Agent Asia (n=497) China (n=138) MIC 90 (mg/L)S (%)MIC 90 (mg/L)S Ampicillin>869.4**192.8 Amox-clavulanate299.6192.8 Cefuroxime-axetil>498.4162.9 Ceftriaxone≤0.015100≤0.015100 Clarithromycin1667.81662.3 Azithromycin 299.8499.3 Levofloxacin0.0399.60.03100 Trimeth-sulfa>452.7>446.4

19. RTI pathogens: Pseudomonas aeruginosa GLOBAL* Surveillance study *Global Landscape On the Bactericidal Activity of Levofloxacin CLSI breakpoints (M100-S17) Agent Asia (n=144) S (%) Piper/tazb76.8 Ceftazidime68.7 Imipenem75.7 Amikacin88.2 Levofloxacin77.1 Ciprofloxacin71.5

20. Antibiotic 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 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…

21. 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

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

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

24. Acute exacerbation of chronic bronchitis (AECB) Bacterial load >10 6 cfu/ml >10 7 cfu/mlepithelial lining fluid modified from Sethi and Murphy. Clin Microbiol Rew 2001; 14:336-63 bronchoscopy samples % of patients

25. Bacterial load and FEV 1 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 (10 7.47 cfu/ml to 10 7.93 cfu/ml, p=0.019)  decline in pulmonary function (FEV 1 ) (p=0.001) Wilkinson et al. Am J Resp Crit Care Med 2003; 167:1090-5

26. 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 treatment Selection of resistant mutant High bacterial load (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

27. Antibiotic 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 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… Surpass the MPCs

28. 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)

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

30.  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?

31. 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 Mutant prevention concentration and window of selection

32. 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 % of isolates This data should be analyzed with pharmacokinetic data

33. Streptocccus pneumoniae Plasma and intrapulmonary concentrations of levofloxacin % of isolates Compartment Concentrations of levofloxacin at 4h after administration 500 mg750 mg Plasma5.2911.98 ELF9.9422.12 AMs97.90105.10 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

34. S. pneumoniae – MPC and pharmacokinetics of different fluoroquinolones MOXIFLOXACIN GATIFLOXACIN LEVOFLOXACIN Hernsen et al. Antimicrob Agents Chemother 2005; 49:1633-35 Compartment Concentrations of levofloxacin at 4h after administration 500 mg750 mg Plasma5.2911.98 ELF9.9422.12 AMs97.90105.10 ELF: epithelial lining fluid AM: alveolar macrophages Gotfried et al. Chest 2001; 119:1114-22

35. 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

36. P. aeruginosa: fluoroquinolone MPCs and ELF concentrations García-Castillo, Morosini, Baquero, Oliver, Baquero, Cantón. 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

37. Antibiotic 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 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…

38. Concentration Time t 1/2 C max t max PK / PD parameters of clinical efficacy MIC AUC : MIC Cmax : MIC T exposition Aminoglycosides Fluoroquinolones Tetracyclines Glicopeptides Fluoroquinolones Beta-lactams Macrolides Linezolid

39. Metlay et al. Emerg Infect Dis 2006; 12:183-190 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

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

41. AUC:MIC Levofloxacin 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

42.  Susceptibility rates (recent surveillance studies a ) among respiratory pathogens based on PK/PD breakpoints a: SENTRY, ARISE, Alexander Project, Protekt Canut et al. J Antimicrob Chemother 2007; 60:607-12

43. 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: 3325–30

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

45. Antimicrobial guidelines for RTI: CAP & AECB  Evidence- or consensus-based guidelines 1  Adapted to - suspected or demonstrated pathogen - severity of illness and co-moribities - previous antibiotic use 2  Often recommend broad-spectrum agents but recent work in antibiotic stewardship promotes narrow-spectrum agents 3,4  Not yet completely updated with recent Pk/Pd knowledge and current resistance trends (should be locally revised) 1 Blasi et al. Pulm Pharm & Therap 2006; 361-9 2 Mandel et al. Clin Infec Dis 2007; 44:S27-72 3 Dryden et al. J Antimicrob Chemoter 2009; 64:1123-5 4 Lim et al. Thorax 2009; 24 (Suppl 3):iii1-55

46. Antimicrobial guidelines for RTI Community acquired pneumonia (British Thoracic Society) SeverityTreatment site First line treatment Alternative treatment LowHome Hospital AmoxicillinDoxycicline ModerateHospitalAmoxicillin + clarithromycin Doxycicline HighHospital (including ICU) Amox/clavulanicPenicilin + levofloxacin or ciprofloxacin Cefuroxime or cefotaxime + clarithromycin Lim et al. Thorax 2009; 64 (Suppl 3): iii1-55

47. Antimicrobial guidelines for RTI Community acquired pneumonia (Japanese Respiratory Society) MaDOI: 10.2169/internalmedicine.45.1691 Outpatient Amoxicillin Penicillin + β-inhibitor Inpatient Penicillin (iv) Cephems (iv) Outpatient 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)

48. Antimicrobial guidelines for RTI Community acquired pneumonia (ATS/IDSA) Mandel et al. Clin Infec Dis 2007; 44:S27-72 PatientTreatment OutpatientPreviously healthyMacrolides or doxycycline Comorbidities Regions with ↑ macrolide R Fluoroquinolone β-lactam + macrolides InpatientsNon-ICUFluoroquinolone or β-lactam + macrolide ICUβ-lactam + macrolide or fluoroquinolone Specific pathogens P. aeruginosa CA-MRSA antipneumococcal-antipseudomonal β-lactam + fluoroquinolone or β-lactam + aminoglycoside + macrolide + vancomycin or linezolid

49. 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

50.  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 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 Respiratory tract infections: CAP & AECB Conclusions

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

52. Fluoroquinolones

53. Fluoroquinolones: spectrum of activity

54. quinolonic ring levofloxacin ciprofloxacin moxifloxacin garenoxacin

55. A well-balanced fluroquinolone … - antimicrobial activity - pharmacokinetic/ pharmacodynamic parameters - adverse effects Levofloxacin

56. Pharmacokinetics Absorption Distribution Metabolism Excretion Pharmacodynamics Spectrum of activity Bactericidal activity - Time-dependency - Concentration- dependency Effect Time PK - PD Effect vs time Antibiotic Clinical efficacy Resistance avoidance Antimicrobial use…

57. Yu et al. Antimicrobial Therapy & Vaccines. 2005 (2nd ed) Pharmacokinetics of fluoroquinolones

58. Gotfried et al. Chest 2001; 119:1114-1122Capitano et al. Chest 2004; 125:965-73 Healthy adults Elderly patients Steady-state concentrations (at 4 h after last dose of 5 days)

59. Gotfried et al. Chest 2001; 119:1114-22Capitano et al. Chest 2004; 125:965-73 Healthy adults Elderly patients Steady-state concentrations (at 4 h after last dose of 5 days) Pharmacokinetics of fluoroquinolones

60. Levofloxacin: optimal bioavailability for sequential therapy Furlanut et al. J Antimicrob Chemother 2003; 51:101-6 Pharmacokinetics of fluoroquinolones

61. 1 Gotfried et al. Chest 2001; 119:1114-22; 2 Weinrich et al. IJAA 2006; 28:221-5; 3 Drusano et al. AAC 2000; 2046-51; 4 Pea et al. PR 2007; 55:38-41; 5 Swoboda et al. JAC 2003; 51:459-62; 6 Rimmele et al. JAC 2004; 533-5; 7 Oberdorfer et al. 2004; 54:836-9; 8 García-Vázquez et al. EJCMID 2007; 26:137-40; 9 Scotton et al. CID 2001; 33:e109-11 Penetration of levofloxacin in different compartments Levofloxacin pharmacokinetics Ratio to serum Macrophages 18.5 1 Liver 3.7 2 Prostate 2.9 3 Sinus 2.5 4 Epithelial lining fluid 1.8 1 Gall bladder 1.8 5 Pleural fluid 1.3 5 Synovial fluid 1.2 6 Diabetic foot >1 7 Bone 1 6 Aqueous humor 0.3 8 CSF 0.3 9 accumulation of levofloxacin in most compartments results in concentrations 10-50-fold greater than the mean MIC of most potential pathogens

62. Levofloxacin  The big issue... - 500 mg / 24 h versus 500 mg / 12 h bid or 750 mg / 24 h  The answers?... - PK/PD - resistant development avoidance

63. Levofloxacin pharmacokinetics Drussano et al. Antimicrob Agents Chemother 2002; 46: 586-9 Epithelial lining fluid/plasma concentration ratio (750 mg/24 h orally 5 days) Montecarlo simulation

64. Levofloxacin Steady-state concentrations (after 2 days of therapy) in critically ill patients with severe community-acquired pneumonia Bosselli et al. Crit Care Med 2005; 33:104-9

65. Forrest et al. Antimicrob Agents Chemother 1993; 37:1073-81 AUC : MIC >125  Ciprofloxacin (200 mg/12 h – 400 mg/8 h i.v.) clinical and microbiological outcome in critically ill ICU patients with Gram negative infections Ciprofloxacin 9* 10 16 7 22 *number of patients

66. AUC : MIC >33.7  Levofloxacin (500 mg/24 h) clinical and microbiological outcomes in patients with community acquired S. pneumoniae respiratory tract infection Levofloxacin Ambrose et al. Antimicrob Agents Chemother 2001; 45:2793-7

67.  Probability of target attainment (AUC:MIC >33.7) for levofloxacin (500 mg/24 h, orally) in patients with community acquired Streptococcus pneumoniae respiratory tract infections Classification and Regression Tree (CART) analysis Ambrose et al. Antimicrob Agents Chemother 2001; 45:2793-7 Levofloxacin