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: 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 reduction in 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processes § Antibiotic used based in PK/PD (pharmacokinetic/ pharmacodynamic) knowledge These recommendations are not out of date…
November, 18 th
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 reduction in 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processes § Antibiotic used based in PK/PD (pharmacokinetic/ pharmacodynamic) knowledge These recommendations are not out of date…
Respiratory tract infection pathogens Micro-organisms Haemophilus influenzae Streptococcus pneumoniae Staphylococcus aureus Pseudomonas aeruginosa Other NFGNB Mycoplasma pneumoniae Chlamydophila pneumoniae Pathogenic colonization Acute Pneumo nia Exacerbatio n (COPD) Bronchiecta sis + ++++ +++ ++ ++
Respiratory tract infection pathogens S. pneumoniae H. influenzae M. catarrhalis P. aeruginosa With resistance problems M. pneumoniae C. pneumoniae L. pneumophila Without resistance problems
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
Streptococcus pneumoniae Invasive isolates Penicillin resistance (I+R) 2000 http: //www. rivm. nl/earss/ 2008
S. pneumoniae Decrease of penicillin (I + R) resistance 2000 2008 I 21. 6 15. 7 R 11. 0 TOTAL 32. 6 SPAIN http: //www. rivm. nl/earss/ 7. 1 22. 8
RTI pathogens: Streptococcus pneumoniae § Regional trends of penicillin resistance (PROTEKT Study) China, Hong Kong, Japan, South Korea and Taiwan Australia Far East n = 657 n = 5155 Latin America n = 2889 North America n = 4155 Northern Europe n = 7170 Southern Europe n = 5479 South Africa n = 1611 Felmingham, Cantón, Jenkins. J Infec 2007; 55: 111 -8
RTI pathogens: Streptococcus pneumoniae Prevalence of resistance (%) § Regional trends of erythromycin resistance (PROTEKT Study) China, Hong Kong, Japan, South Korea and Taiwan Australia Far East n = 657 n = 5155 Latin America n = 2889 North America n = 4155 Northern Europe n = 7170 Southern Europe n = 5479 South Africa n = 1611 Felmingham, Cantón, 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, Cantón, Jenkins. J Infec 2007; 55: 111 -8
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, 111 e 118 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 erythromycin-R genes § Absence of fluoroquinolone resistance § Population structure: - 75% of the isolates belonging to 19 F, 14, 23 F, 6 B and 19 A serotypes - dispersion of international resistant clonal complexes: - Taiwan 19 F-14 - Spain 23 F-1, - Spain 6 B-2 - Taiwan 23 F-15 Yang et Int J Antimicrob Agenst Chemother 2008; 32: 386 -91
RTI pathogens: Streptococcus pneumoniae GLOBAL* Surveillance study Asia (n=564) China (n=105) MIC 90 (mg/L) S (%) Penicillin 4 40. 1 4 53. 3 Amox-clavulanate >4 80. 9 >4 84. 8 Cefuroxime-axetil >4 46. 5 >4 62. 9 Ceftriaxone 2 74. 1 2 81. 0 Azithromycin >4 22. 5 >4 10. 5 Levofloxacin 1 98. 0 1 99. 0 Trimeth-sulfa >4 38. 3 >4 26. 7 Agent CLSI breakpoints (M 100 -S 17) *Global Landscape On the Bactericidal Activity of Levofloxacin
RTI pathogens: Haemophillus influenzae GLOBAL* Surveillance study Asia (n=497) China (n=138) MIC 90 (mg/L) S (%) MIC 90 (mg/L) S Ampicillin >8 69. 4** 1 92. 8 Amox-clavulanate 2 99. 6 1 92. 8 Cefuroxime-axetil >4 98. 4 1 62. 9 ≤ 0. 015 100 Clarithromycin 16 67. 8 16 62. 3 Azithromycin 2 99. 8 4 99. 3 Levofloxacin 0. 03 99. 6 0. 03 100 Trimeth-sulfa >4 52. 7 >4 46. 4 Agent Ceftriaxone CLSI breakpoints (M 100 -S 17): **29. 8% β-lactamase (+); 0. 8 amp-R β-lactamase (-) *Global Landscape On the Bactericidal Activity of Levofloxacin
RTI pathogens: Pseudomonas aeruginosa GLOBAL* Surveillance study Agent Asia (n=144) S (%) Piper/tazb 76. 8 Ceftazidime 68. 7 Imipenem 75. 7 Amikacin 88. 2 Levofloxacin 77. 1 Ciprofloxacin 71. 5 CLSI breakpoints (M 100 -S 17) *Global Landscape On the Bactericidal Activity of Levofloxacin
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 reduction in 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…
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
Bacterial inoculum and RTI Vicious Cycle Mensa & Trilla Clin Microbiol Infect 2006; (Suppl 3): 42 -54
Bacterial inoculum and RTI § Failure in bacterial eradication determines clinical failure in AECB % of clinical failure Meta-analysis: 12 studies, 16 antibiotics R=0. 83 Rate of eradication failure Pechère. Infect Med 1998; 15 (Suppl E): 46– 54
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 (107. 47 cfu/ml to 107. 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
Bacterial inoculum in RTI § Why is so important erradication for the clinical outcome? the bronchitis exacerbation model Acute exacerbation resolution antibiotic treatment Decrease of bacterial load Low bacterial load (susceptible) natural resistant mutants (10 -8) High bacterial load (susceptible) Decrease of neutrophil inflammation Decrease of bacterial injury Decline in pulmonary function Recurrent exacerbation status antibiotic treatment Selection of resistant mutant Increase of bacterial injury Increase the risk of resistance Increase of bacterial variation
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 reduction in 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…
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 bacterial inoculum susceptible bacteria resistant bacteria § Under antibiotic pressure the susceptible subpopulation is inhibited and the resistant mutants can survive and become dominant within the population (selection)
antibiotic The resistant subpopulation may emerge under the action of an antimicrobial 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 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 ? on i t c e - MIC of the resistant population sel f o ow d n i w
Mutant prevention concentration and window of selection Baquero & Negri. Bio. Essays 1997; 19: 731 -6 Drlica K. ASM News 2001; 67: 27 -33 Cantón et al. Inter J Antimicrob Chemother 2006; 28 (Suppl 2): S 115 -27
S. pneumoniae, mutant prevention concentration (MPC) § Potential for restricting the selection of resistant mutants moxifloxacin > gatifloxacin > levofloxacin % of isolates Blondeau et al. Antimicrob Agents Chemother 2001; 45: 433 -8 This data should be analyzed with pharmacokinetic data
Streptocccus pneumoniae Plasma and intrapulmonary concentrations of levofloxacin % of isolates Compartment Concentrations of levofloxacin at 4 h after administration 500 mg 750 mg Plasma 5. 29 11. 98 ELF 9. 94 22. 12 AMs 97. 90 105. 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
S. pneumoniae – MPC and pharmacokinetics of different fluoroquinolones Compartment MOXIFLOXACIN GATIFLOXACIN LEVOFLOXACIN Hernsen et al. Antimicrob Agents Chemother 2005; 49: 1633 -35 Concentrations of levofloxacin at 4 h after administration 500 mg 750 mg Plasma 5. 29 11. 98 ELF 9. 94 22. 12 AMs 97. 90 105. 10 ELF: epithelial lining fluid AM: alveolar macrophages Gotfried et al. Chest 2001; 119: 111
P. aeruginosa – mutant prevention concentration (MPC) García-Castillo, Morosini, Baquero, Oliver, Baquero, Cantón. 15 th ECCMID, Prague, 2004 Hansen et al. Int J Clin Microbiol Infect Dis 2006; 27: 120 -140
P. aeruginosa: fluoroquinolone MPCs and ELF concentrations 1000 LEVOFLOXACIN µg/ml 100 22. 1 µg/ml (750 mg/24 h) 17. 8 µg/ml (500 mg/12 h) 9. 9 µg/ml (500 mg/24 h) 10 1 0. 01 MPC MIC 1000 CIPROFLOXACIN µg/ml 100 Epithelial lining fluid concentration (ELF) Gotfried et al. Chest 2001; 119: 1114 -22 Boselli et al. Crit Care Med 2005; 33: 104 -9 10 2. 3 µg/ml (750 mg/24 h) 1. 8 µg/ml (500 mg/12 h) 1 0. 01 strains García-Castillo, Morosini, Baquero, Oliver, Baquero, Cantón. 15 th ECCMID, Prague, 2004
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 reduction in 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…
PK / PD parameters of clinical efficacy Concentration Cmax : MIC Aminoglycosides Fluoroquinolones Tetracyclines AUC : MIC Glicopeptides t 1/2 Fluoroquinolones MIC Beta-lactams Texposition tmax Time Macrolides Linezolid
• 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
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
AUC: MIC Levofloxacin and S. pneumoniae CMI 3. 2 2. 6 1. 8 1. 4 In vitro pharmacokinetic simulated model Lister PD. Diagn Microbiol Infect Dis 2002; 44: 43 -9
§ 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
Which is the influence of these recommendations on current antimicrobial guideline for RTI infections
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 et al. Clin Infec Dis 2007; 44: S 27 -72 3 Dryden et al. J Antimicrob Chemoter 2009; 64: 1123 -5 4 Lim et al. Thorax 2009; 24 (Suppl 3): iii 1 -55 2 Mandel
Antimicrobial guidelines for RTI Community acquired pneumonia (British Thoracic Society) Severity Treatment site Low Home Hospital First line treatment Alternative treatment Amoxicillin Doxycicline Moderate Hospital Amoxicillin + clarithromycin Doxycicline High Amox/clavulanic Penicilin + levofloxacin or ciprofloxacin Hospital (including ICU) Cefuroxime or cefotaxime + clarithromycin Lim et al. Thorax 2009; 64 (Suppl 3): iii 1 -55
Antimicrobial guidelines for RTI Community acquired pneumonia (Japanese Respiratory Society) Outpatient Amoxicillin Penicillin + βinhibitor Inpatient Penicillin (iv) Cephems Outpatient Macrolides Tetracyclin es Inpatient Minocyclin e (iv) Macrolides Outpatient Amoxicillin High doses Adpated to speficic pathogen Carbapanems (iv) + new quinolone (iv) Inpatient or Penicillin macrolide (iv) Minoclycline Cephems (ivi) Ma. DOI: 10. 2169/internalmedicine. 45. 1691 (iv)
Antimicrobial guidelines for RTI Community acquired pneumonia (ATS/IDSA) Patient Outpatie nt Inpatient s Treatment Previously healthy Macrolides or doxycycline Comorbidities Regions with ↑ macrolide. R Fluoroquinolone β-lactam + macrolides Non-ICU Fluoroquinolone or β-lactam + macrolide ICU β-lactam + macrolide or fluoroquinolone Specific pathogens P. aeruginosa CA-MRSA antipneumococcalantipseudomonal β-lactam + fluoroquinolone or β-lactam + aminoglycoside + Mandel et al. Clin Infec Dis 2007; 44: S 27 -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 Initiative for Chronic Obstructive Lung Disease.
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 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
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
Fluoroquinolones
Fluoroquinolones: spectrum of activity
quinolonic ring ciprofloxacin moxifloxacin levofloxacin garenoxacin
Levofloxacin A well-balanced fluroquinolone … - antimicrobial activity - pharmacokinetic/ pharmacodynamic parameters - adverse effects
Antimicrobial use… Antibiotic PK - PD Pharmacokinetics Absorption Distribution Metabolism Excretion Effect • • Effect vs time Clinical efficacy Time Pharmacodynamics • Spectrum of activity • Bactericidal activity - Time-dependency - Concentrationdependency Resistance avoidance
Pharmacokinetics of fluoroquinolones Yu et al. Antimicrobial Therapy & Vaccines. 2005 (2 nd ed)
Pharmacokinetics of fluoroquinolones Steady-state concentrations (at 4 h after last dose of 5 days) Healthy adults Gotfried et al. Chest 2001; 119: 1114 -1122 Elderly patients Capitano et al. Chest 2004; 125: 965 -73
Pharmacokinetics of fluoroquinolones Steady-state concentrations (at 4 h after last dose of 5 days) Healthy adults Gotfried et al. Chest 2001; 119: 1114 -22 Elderly patients Capitano et al. Chest 2004; 125: 965 -73
Pharmacokinetics of fluoroquinolones Levofloxacin: optimal bioavailability for sequential therapy Furlanut et al. J Antimicrob Chemother 2003; 51: 101 -6
Levofloxacin pharmacokinetics Ratio to serum Penetration of levofloxacin in different compartments accumulation of levofloxacin in most compartments results in concentrations 10 -50 -fold greater than the mean MIC of most potential pathogens 1 Gotfried Macrophages Liver Prostate Sinus Epithelial lining fluid Gall bladder Pleural fluid Synovial fluid Diabetic foot Bone Aqueous humor CSF 18. 51 3. 72 2. 93 2. 54 1. 81 1. 85 1. 35 1. 26 >17 16 0. 38 0. 39 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-
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
Levofloxacin pharmacokinetics Epithelial lining fluid/plasma concentration ratio (750 mg/24 h orally 5 days) Montecarlo simulation Drussano et al. Antimicrob Agents Chemother 2002; 46: 586 -9
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
Ciprofloxacin § Ciprofloxacin (200 mg/12 h – 400 mg/8 h i. v. ) clinical and microbiological outcome in critically ill ICU patients with Gram. AUC : MIC negative infections >125 *number of patients 9* 16 7 22 10 Forrest et al. Antimicrob Agents Chemother 1993; 37: 1073 -81
Levofloxacin § Levofloxacin (500 mg/24 h) clinical and microbiological outcomes in patients with community acquired S. pneumoniae respiratory tract AUC : MIC infection >33. 7 Ambrose et al. Antimicrob Agents Chemother 2001; 45: 2793 -7
Levofloxacin § 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
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