Combination antibiotic therapy bacteremic pneumococcal pneumonia: PRO
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Combination antibiotic therapy bacteremic pneumococcal pneumonia: PRO Presentation Transcript

  • 1. Combination antibiotic therapy bacteremic pneumococcal pneumonia: PRO Antoni Torres. Universitat de Barcelona. Spain
  • 2. IDSA/ATS Clin Infect Dis 2007;44:S27-72
  • 3. Outline
    • Why combination therapy?
    • What agents?
    • For how long?
    • Is combination therapy enough?
  • 4. Pneumococcal pneumonia
    • Two retrospective studies (1,2) and a prospective study (3) have observed a lower mortality in patients with community-acquired bacteraemic pneumococcal pneumonia treated with combination therapy compared with subjects treated with only one antimicrobial
    • One retrospective study (4) concluded that combination antibiotic therapy does not decrease mortality in patients with severe pneumococcal infection
    ( 1) Arch Inter Med 2001; 161: 1837-1842 (3) Am J Resp Crit Care Med 2004; 170: 440-444. (2) Clin Infect Dis 2003; 36: 389-395. (4) Eur J Clin Microbiol Infect Dis. 2005; 24: 688-690.
  • 5. 14-d mortality Combination therapy: 23.4% Monotherapy: 55.3% p = 0.0015
  • 6. Combination therapies prescribed in critically ill patients
    • ß-lactam/macrolide 14
    • Vancomycin/ß-lactam 12
    • ß-lactam/aminoglycoside 7
    • vancomycin/other antibiotic 4
    • ß-lactam/quinolone 4
    • double ß-lactam therapy 2
    • ß-lactam/chloramphenicol 2
    • ß-lactam/TMP-SMX 1
    • Clindamycin/quinolone 1
  • 7.
      • Retrospective study of a cohort of 1,840 adult patients with severe sepsis or septic shock enrolled in two multicenter clinical trials
        • 107 patients with monobacterial pneumococcal sepsis
        • 75 patients with bacteremic pneumococcal pneumonia
  • 8. Community-acquired pneumonia with shock
    • Prospective observational study. 33 Spanish ICUs
    • 529 patients were enrolled, of whom 270 (51%) developed septic shock.
    • Monotherapy (n = 52)
      • Β -lactam (n=25; 48.2%)
      • Fluoroquinolone (N=22; 42.2%)
      • Macrolides were not administered in monotherapy.
    • Combination therapies
      • β -lactam/macrolides (n = 131; 48.5%)
      • β -lactam/fluoroquinolones (n = 54; 20.0%).
    Rodriguez A. Crit Care Med 2007; 35: 1493-1498
  • 9. Community-acquired pneumonia with shock Rodriguez A. Crit Care Med 2007; 35: 1493-1498
    • Survival was higher for both antibiotic combinations
    • β -lactam plus macrolide (HR, 1.73; 95% CI, 1.08–2.76; p = .02)
    • β -lactam plus fluoroquinolones (HR, 1.77; 95% CI, 1.01–3.15; p = .05).
  • 10. Levofloxacin as monotherapy in severe CAP
    • Prospective, randomized 1:1, comparative, open trial
    • 398 randomized patients who had been admitted to the ICU with severe CAP without shock.
      • Monotherapy: Levofloxacin
      • Combination therapy: Cefotaxime plus ofloxacin
    • Clinical efficacy, bacteriologic response and mortality was similar in both group
    Chest. 2005; 128:172-183.
  • 11. Patients on MV Although in patients on MV, the cure rate and overall mortality rates were not statistically different in both treatment groups, the noninferiority of L to C + O could not be demostrated. Chest. 2005; 128:172-183.
  • 12. Β -lactam and Macrolide Combination Therapy vs. Fluoroquinolone Monotherapy BL+M F BL+M F Antimicrob Agents Chemother 2007; 51: 3977-3982. 0 30 50 10 20 40 Mortality (%) PSI 4 PSI 5 p=0.6 p=0.05
  • 13. What agents? Macrolides or fluoroquinolones? That’s the question .
  • 14. 172 episodes of severe CAP Multivariate analysis. 30-day Mortality B-lact+fluoroq OR 2.71 (95%IC 1.2-6.1)
  • 15.
      • Retrospective analysis of 2,209 Medicare patients with bacteremic pneumonia
        • Initial use of any antibiotic active against atypical organisms was independently associated with a decreased risk of 30-day mortality
        • the benefits of atypical treatment were associated with the use of macrolides, but not the use of fluoroquinolones or tetracyclines
  • 16.
            • Critical care patients: 20%
  • 17. Outcome of intubated patients with CAP: Impact on outcome of combination antibiotic with macrolides
    • Eu-VAP/CAP study: 218 patients on invasive mechanical ventilation for CAP
    • Monotherapy was given in 43 (19.7 %) and combination therapy in 175 (80.3%) patients
    • Empirical antibiotic therapy was in accordance with 2007 IDSA/ATS guidelines in 100(45.9%) patients
      • Macrolides 46 patients
      • Fluoroquinolones: 54 patients
    I. Martin-Loeches et al, Intensive Care Med 2010
  • 18. Cox regression analysis
    • Macrolide use was associated with lower ICU mortality (HR 0.48 95%CI 0.23-0.97, p = 0.04) when compared to the use of fluoroquinolones.
    • Patients with severe sepsis or septic shock (n=92): Similar results (HR 0.44 95%CI 0.20-0.95, p = 0.03)
    I. Martin-Loeches et al, Intensive Care Med 2010 macrolides macrolides quinolones quinolones
  • 19.  
  • 20. S pneumoniae resistance (Barcelona) Am J Resp Crit Care Med 1999; 159: 1835-1842 Chest 2006; 130: 800-806 Penicillin Cefotaxime Eritrhomycin *Significant difference 0 20 60 100 80 40 Resistance (%) 1999-2002 (N= 123) 1996-1998 (N=101) * *
  • 21. Potential Mechanisms for Mortality Reduction in severe CAP
    • Uncovered pathogen with monotherapy
    • Altered antibiotic pharmacokinetics during critical illness
    • Immunomodulatory effects of macrolides
  • 22. Immunomodulatory effects of macrolides
    • Pro-inflammatory effects of macrolides
      • Enhance phagocytosis
    • Anti-inflammatory effects of macrolides
      • Inhibit iNOS gene expression and NO release
      • Inhibit the expression of ICAM, thereby modulating the recruitment of neutrophils to inflamed sites
      • Inhibit NF- B activation leading to decreased production of cytokines (TNF-  , IL-1, IL-6 and IL-8)
      • Inhibit reactive oxygen species production
  • 23. Virulence factors of S pneumoniae
  • 24. Macrolides and pneumolysin production
    • Pneumolysin is one of the most important virulence factors of S. pneumoniae .
      • It augments intrapulmonary growth and dissemination during the early pathogenesis of S. pneumoniae .
      • It disrupts epithelial tissues that form a mechanical barrier, and allow S. pneumoniae to penetrate into the blood stream.
    • Macrolides attenuate the production of pneumolysin by both macrolide-susceptible and macrolide-resistant strains of Streptococcus pneumoniae
    Eur Respir J. 2006;27:1020-5 J Antimicrob Chemother. 2007; 59:224-9
  • 25. Is azithromycin the first choice macrolide for CAP?
        • Patients with CAP who received ceftriaxone combined with a 3-day course of azithromycin or a 10-day course of clarithromycin were compared in an open-label, prospective study
        • Of 896 assessable patients, 220 received clarithromycin and 383 received azithromycin.
        • There were no significant differences between groups with regard to the severity of illness or the incidence of bacteremia
    Clin Infect Dis 2003; 36:1239-1245.
  • 26. Patients with CAP who do not require ICU admission Length of stay (days) AZT CLT 0 6 10 2 4 8 Mortality (%) AZT CLT Clin Infect Dis 2003; 36:1239-1245. 0 6 10 2 4 8
  • 27.  
  • 28. For how long?
    • No previous study has been designed to determine the optimal duration of combination therapy
    • Current guidelines do not establish duration of combination therapy
    • Once the etiology of CAP has been identified on the basis of reliable microbiological methods, antimicrobial therapy should be directed at that pathogen. (Moderate recommendation; level III evidence.IDSA)
  • 29. Combination therapy: 3-5 days
    • “ If our conclusions are confirmed by other prospective studies, we recommend that clinicians target combination antibiotic treatment only for those patients who are critically ill, and limit the duration of the combination to 3–5 days ”.
  • 30. Delay of antimicrobial therapy and mortality Arch Intern Med 2004; 164: 637-644
  • 31. Kumar, et al. Crit Care Med 2006;34:1589–1596 Risk of death with increasing antimicrobial delay: subgroups X, delay (hours) Adjusted odds ratio of death 1.0 1.1 1.2 1.3 All Documented Suspected Culture + Culture - Bacteraemia + Bacteraemia - Community Nosocomial Gram + Gram - Fungal Respiratory Urinary tract Intra-abdominal Skin/soft tissue 1385 769 608 1546 459 1695 2154 N 912 1242 768 584 838 131 230 156 641
  • 32. Bacteremic pneumococcal CAP 125 episodes
    • Independent risk factors associated with in-hospital mortality.
    • aHR CI 95% p
    • Charlson comorbidity index 1.13 (0.98 - 1.32) 0.131
    • Sepsis severe/ septic shock 5.06 (1.631 – 15.71) 0.005
    • 1st adequate atb ≥ 4 hours 2.62 (1.06 - 6.45) 0.037
    • Independent risk factors associated with mortality at 90 days
    • HRa CI 95% p
    • Charlson comorbidity index 1.17 (1.02 - 1.34) 0.023
    • Sepsis severe / septic shock 3.03 (1.22 – 7.51) 0.016
    • 1st adequate atb ≥ 4 hours 2.21 (1.01 - 4.86) 0.048
    Scand J Infect Dis 20010(accepted)
  • 33. Bacteremic pneumococcal CAP 125 episodes
    • The use combination therapy was not included in these models but was a protective factor for delayed adequate therapy [aHR 0.53 (95% CI 0.29-0.95); p =0.033].
    Scand J Infect Dis 2010 (accepted)
  • 34. Conclusions
    • Combination therapy is mandatory in all patients with severe CAP and particularly in case of bacteremic pneumococcal pneumonia
    • As in other patients with severe sepsis, early administration of adequate therapy is also crucial in these patients
  • 35. Conclusions
    • A macrolide might be a superior option than a fluoroquinolone to be added to a  -lactam agent
    • Macrolides might lessen the inflammatory response generated by microbial proliferation and increased by treatment with a  -lactam agent