Severe pneumococcal pneumonia: impact of new quinolones on prognosis

Streptococcus pneumoniae is the leading causative agent of community-acquired pneumonia (CAP). Despite new antimicrobial agents and advances in supportive measures, attributable mortality linked to pneumococcal pneumonia remains unchanged and dramatically high when patient are admitted in intensive care units (ICU) [1].

Most guidelines have been proposing, for more than 15 years, a combination of a β-lactam with either a quinolone or a macrolide as empirical, first-line therapy of severe CAP requiring ICU admission [2–8]. Although a recent study demonstrated combination antibiotic therapy to be associated with a higher survival rate than monotherapy in patients with severe CAP and shock [9], the rationale for this combination was not to increase efficacy but rather to routinely provide coverage of all common pathogens causing severe CAP and particularly, S. pneumoniae and Legionella species.

In our ICU, we followed until 2003 the 1991 French recommendations [2]. Most patients received an empirical therapy based on a β-lactam-fluoroquinolone combination. Before 2003, fluoroquinolones used were ofloxacin and ciprofloxacin. Levofloxacin replaced these quinolones since its 2003 addition to the hospital formulary. Such a replacement was comforted by the ERS, French and IDSA guidelines published between 2005 and 2007 [6–8]. We wished to determine outcomes of patients treated with a combination of β-lactam plus fluoroquinolone for severe pneumococcal pneumonia. This homogenous modification of severe CAP antibiotic management in our ICU gives us the further opportunity to assess the influence of a fluoroquinolone with enhanced activity against S.pneumoniae.

During the study period, 378 patients with severe CAP were admitted in our unit. Among them, 83 (22%) patients exhibited a severe pneumococcal pneumonia and, finally, we identified 70 patients treated with a β-lactam combined with a fluoroquinolone, including 53 men (75.7%) and 17 women (24.3%). The mean age was 63.8 ± 16.8 years. S. pneumoniae was identified in blood cultures in 25 patients (35.7%). Infection was polymicrobial in 18 patients (25.7%). Causative pathogens associated with S. pneumoniae were Haemophilus influenzae (n = 7), methicillin susceptible Staphylococcus aureus (n = 4), enterobacteriaceae (n = 4), Streptococcus spp. (n = 2) and Moraxella catarrhalis (n = 2). All pathogens were susceptible to at least one drug (β-lactam and/or fluoroquinolone) received by the patients. Thirty-eight patients (54.3%) were classified as Group A. β-lactams used were a third generation cephalosporin (n = 20; 52.6%), amoxicillin ± clavulanic acid (n = 16; 42.1%) and piperacillin-tazobactam (n = 2; 5.3%) combined with ofloxacin (n = 33; 86.8%) or ciprofloxacin (n = 5; 13.2%). Thirty-two patients (45.7%) were classified as Group B. β-lactams used were a third generation cephalosporin (n = 26; 81.3%), amoxicillin ± clavulanic acid (n = 5; 15.6%) and piperacillin-tazobactam (n = 1; 3.1%) combined with levofloxacin.

On Day 15, 14 (20%) patients had died, 12 (31.6%) in Group A and 2 (6.3%) in Group B (p = 0.02).

Overall, 26 patients died in the ICU, 17 (44.8%) in group A vs. 9 (28.1%) in group B (p = 0.15). So, difference in mortality rates was only significant during the first 15 days of ICU stay (Figure 1). In Group A, in-ICU mortality was 45% (9/20) when ofloxacin or ciprofloxacin were combined with a third generation cephalosporin and 44.4% (8/18) when combined with another beta-lactam, respectively (p = 0.97). In group B, it was 26.9% (7/26) when levofloxacin was combined with a third generation cephalosporin and 33.3% (2/6) when combined with another beta-lactam (p = 1).

According to the results of the bivariate analysis, the following variables were entered in the stepwise analysis: chronic heart failure, age > 70 yrs, acute respiratory failure requiring mechanical ventilation, septic shock on ICU admission, use of hydrocortisone, haemodialysis, PSI score = 5, SAPS II > 50 on D1, LOD > 8 on D1, SOFA >8 on D1 and initial treatment with a β-lactam combined with ofloxacin or ciprofloxacin (Group A).

Three independent factors associated with outcome at ICU discharge were identified: septic shock on ICU admission (AOR = 10.6; 95% CI 2.87- 39.3; p = 0.0004), age > 70 yrs. (AOR = 4.88; 95% CI 1.41-16.9; p = 0.01) and initial treatment with a β-lactam combined with ofloxacin or ciprofloxacin (AOR = 4.1; 95% CI 1.13-15.13; p = 0.03).

The main finding of this retrospective analysis is that levofloxacin plus a β-lactam appears to be associated with improved survival compared to ofloxacin or ciprofloxacin plus a β-lactam in severe pneumococcal CAP.

Empirical antibiotic regimen for ICU-treated severe CAP has long been recommended to cover the 3 most common severe CAP pathogens (S. pneumoniae, S. aureus and H.influenzae), atypical pathogens and most relevant Enterobacteriaceae species. Levofloxacin is a fluoroquinolone active against most of these pathogens, especially S. pneumoniae with or without decreased penicillin susceptibility [18, 19]. Its clinical activity in CAP has been well documented in various clinical trials in Europe and the USA [20, 21]. Some studies demonstrated the efficacy of levofloxacin used as monotherapy in severe CAP, compared to ceftriaxone plus erythromycin or cefotaxime plus ofloxacin [22, 23]. Nevertheless, experts continue to propose, for ICU-treated severe CAP, an empirical antibiotic regimen based on an anti pneumococcal β-lactam combined with either a macrolide or a fluoroquinolone. Since respiratory fluoroquinolones with enhanced activity against S. pneumoniae (levofloxacin, moxifloxacin or gemifloxacin) became available, they replaced second generation fluoroquinolones (ofloxacin or ciprofloxacin) in the guidelines [6–8]. This fluoroquinolone generation shift has never been clearly justified and, to our knowledge, no clinical study has compared these different quinolones combined with a β-lactam in severe CAP. Our results suggest that, when severe CAP causative agent is S. pneumoniae, a combination levofloxacin plus β-lactam is associated with lower mortality than a combination ofloxacin or ciprofloxacin plus β-lactam.

These results could be surprising as all patients received an appropriately dosed β-lactam active against S. pneumoniae and as numerous strains of S. pneumoniae remain in vitro susceptible to ofloxacin or ciprofloxacin. However, there might be bacteriological and clinical data explaining our results. A synergy between β-lactams and levofloxacin against S. pneumoniae has been reported [24]. Conversely, synergy was rarely observed between the combination of cefotaxime and ofloxacin [25]. Recent clinical studies suggest that combination therapies could improve the prognosis of pneumococcal pneumonia: Waterer et al. retrospectively studying 225 patients with severe bacteremic pneumococcal pneumonia demonstrated that a single effective therapy was an independent predictor of mortality (AOR = 6.2) [26]. Baddour et al. performed a prospective, multicenter, international study including 844 adult patients with S. pneumoniae bacteremia [27]. Although the 14-day mortality was not significantly different for all patients receiving monotherapy versus combination (11.5% vs. 10.4%), a combination of in vitro active agents was associated with a significantly lower mortality than a single active agent (19.4% vs. 60%; p = 0.0006).

The present work has numerous limits. The most important is probably major treatment differences among the two groups. Patients were recruited during a long period (1996-2009), during which therapies such as hydrocortisone, drotrecogin alfa (activated), or intensive insulin therapy were introduced. Management of septic shock and ARDS has changed following results of large international studies [28, 29]. As most changes in management of patients with multiple organ failures overlap with our antibiotic policy changes, our results might be biased. Indeed, hydrocortisone use and intensive insulin therapy were more frequent in group B than in Group A. However, these factors were not significantly associated with ICU survival in bivariate analysis and hydrocortisone use, in multivariate analysis, was not an independent prognostic factor.. Moreover, there is no evidence suggesting a survival benefit by most adjunctive therapies in patients with CAP [30] and the benefit of intensive insulin therapy in medical ICU and/or low-dose steroids is now highly questionable [31, 32]. Similarly, the use of cephalosporin is more frequent in group B than in group A. However, the use of a third generation cephalosporin rather than amoxicillin has no impact on prognosis. This is not surprising as, to our knowledge, no clinical study demonstrated a third generation cephalosporin to be superior to amoxicillin for non penicillin-resistant S. pneumoniae CAP as far as drug dosage is adequate. Finally, some important prognostic parameters such as the time elapsed between admission and the first dose of antibiotic were not taken into account in our study. Before 2006, we did not have computerized data charts thus, exact time of admission and antibiotics admission, particularly for patients transferred from other departments/hospitals cannot be obtained.

Our study suggests that levofloxacin combined with a β-lactam is associated with improved survival in comparison with ofloxacin or ciprofloxacin combined with a β-lactam in severe pneumococcal patients admitted in the ICU. This combination, proposed by current guidelines as empirical treatment of severe CAP patients admitted in ICU could improve their prognosis. Obviously, only a prospective, randomized, double-blind trial could confirm this result.