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.
Combination therapies prescribed in critically ill patients
vancomycin/other antibiotic 4
double ß-lactam therapy 2
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
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.
β -lactam/macrolides (n = 131; 48.5%)
β -lactam/fluoroquinolones (n = 54; 20.0%).
Rodriguez A. Crit Care Med 2007; 35: 1493-1498
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).
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.
Combination therapy: Cefotaxime plus ofloxacin
Clinical efficacy, bacteriologic response and mortality was similar in both group
Chest. 2005; 128:172-183.
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.
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
What agents? Macrolides or fluoroquinolones? That’s the question .
172 episodes of severe CAP Multivariate analysis. 30-day Mortality B-lact+fluoroq OR 2.71 (95%IC 1.2-6.1)
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
Critical care patients: 20%
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
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
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) * *
Potential Mechanisms for Mortality Reduction in severe CAP
Uncovered pathogen with monotherapy
Altered antibiotic pharmacokinetics during critical illness
Immunomodulatory effects of macrolides
Immunomodulatory effects of macrolides
Pro-inflammatory effects of macrolides
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
Virulence factors of S pneumoniae
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
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.
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
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)
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 ”.
Delay of antimicrobial therapy and mortality Arch Intern Med 2004; 164: 637-644
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
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