Initial use of one or two antibiotics for critically ill patients with community-acquired pneumonia: impact on survival and bacterial resistance

Community-acquired pneumonia (CAP) is among the most common severe infections in critically ill patients [1] and is associated with a high death toll. Failure to use adequate antibiotics (that is, antibiotics active in vitro on the causative organism) considerably increases the risk of death, particularly in patients with severe sepsis [2, 3]. Consequently, the recommended antibiotic regimen for patients with CAP requiring hospital admission is either a fluoroquinolone alone or a combination of two antibiotics, including a macrolide [4–6]. Many trials suggest greater efficacy of dual therapy (usually with a β-lactam and a macrolide or fluoroquinolone) compared to monotherapy (usually with a β-lactam) [3, 7–15]. Macrolides may be particularly useful, as they blunt the inflammatory response via immunomodulating effects and may exert effects on bacteria not included in their spectrum [16]. However, current recommendations are based chiefly on theoretical grounds, as opposed to high-quality studies [17–19]. Furthermore, a systematic review of randomized controlled trials found no evidence that empirical antibiotic therapy covering atypical pathogens improved survival or clinical efficacy in patients admitted for CAP [18].

Our primary objective in this observational cohort study of a prospective database was to determine whether using two initial antibiotics instead of one improved 60-day mortality in patients admitted to the ICU for CAP. We also assessed the effect on 60-day mortality of receiving adequate antibiotic therapy initially versus secondarily. Subgroup analyses were done in patients with specific organisms and in those with the most severe acute-illness syndromes. The risks of nosocomial pneumonia and multidrug-resistant (MDR) bacteria were compared in patients given one versus two antibiotics.

In a very large cohort of immunocompetent ICU patients with CAP, initial adequate antibiotic therapy improved 60-day survival and the improvement was greatest in the patients with S. pneumoniae infection or septic shock. Initial dual antibiotic therapy (β-lactam plus macrolide or fluoroquinolone) was associated with a higher frequency of adequate initial therapy but was not associated with better 60-day survival compared to β-lactam monotherapy. Dual therapy did not significantly affect the risk of nosocomial pneumonia or MDR bacteria compared to monotherapy.

Our study provides a good picture of the pathogens responsible for CAP requiring ICU admission. The distribution of the pathogens was consistent with previously published results, which vary widely, however, perhaps in relation to variations in case-mix [6]. Thus, the prevalence of S. pneumoniae infection in our study was only about half that found in a vast cohort of 3,523 patients in Spain [27], whereas the prevalence of Gram-negative bacilli was similar. The Spanish study included 15% of outpatients and 85% of inpatients admitted to wards or ICUs, whereas we studied only ICU patients, a population possibly characterized by greater bacterial virulence, greater bacterial resistance, and/or a longer time to treatment. Despite our restrictive inclusion criteria, Enterobacteriaceae and Pseudomonas aeruginosa were identified in 9.2% and 3% of patients, respectively. These pathogens, which raise specific treatment challenges, are typically found in healthcare-associated pneumonia [28]. However, 60-day mortality was independently related to acute illness severity, acute organ dysfunction, the presence of at least one co-morbidity and gender [29], but not to the nature of the pathogens, confirming our previous findings [30].

The better 60-day survival associated with initial adequate antibiotic therapy, particularly in the patients with the greatest disease severity, is consistent with many studies documenting the importance of very early adequate antibiotic administration in septic shock and severe pneumonia [2, 31, 32]. Dual therapy significantly increased the frequency of initial adequate therapy but did not increase survival. This apparent inconsistency in our findings may be ascribable to the fact that adequate therapy in patients without bacteriological documentation was defined in our study as compliance with guidelines. Another possible explanation is insufficient statistical power, although our cohort was large. So the effect of dual therapy in improving initial treatment adequacy may have been too small to induce a significant decrease in mortality.

Our finding that 60-day mortality was not significantly decreased by using two initial antibiotics instead of one, even in patients with septic shock or S. pneumoniae infection, may appear to contradict earlier studies [3, 8, 9, 21]. These discrepancies may be ascribable to differences in disease severity, causative organisms, antibiotics used, exclusion criteria and primary outcome measures. Thus, a prospective observational study of ICU patients found that dual therapy improved survival in the subgroup with shock, whereas no difference with monotherapy was noted in the subgroup without shock; however, survival was recorded at ICU discharge or on Day 28 [3]. In another prospective observational ICU study, in which 75.7% of the patients had shock; dual therapy, including a macrolide, was associated with better ICU survival compared to dual therapy with a fluoroquinolone [8], whereas we found no significant difference in 60-day mortality between these two groups. Although one of these studies excluded patients with COPD [3] and the other excluded patients with immunodeficiencies [8], neither used all the exclusion criteria used in our study. Two other studies focused on S. pneumoniae disease. One was a prospective observational study of patients with S. pneumoniae bacteremia showing that dual therapy improved 14-day survival in the subgroup requiring ICU admission but not in the subgroup managed on the wards [9]. In patients with S. pneumoniae CAP and bacteremia admitted to wards or ICUs, initial dual therapy with a macrolide was associated with better hospital survival compared to a β-lactam alone. Again, these studies had a different case-mix, as only 21.1% of our patients had S. pneumoniae infection and only 12.7% had bacteremia. Two studies found no difference between one and two initial antibiotics in patients with severe CAP [13, 14]. One was a post hoc analysis of data from two clinical trials of patients with severe pneumococcal sepsis and used ICU survival as the primary outcome, [13] whereas the other was a randomized trial comparing lefloxacin alone to ofloxacin plus cefotaxime in patients with severe CAP but with no shock and used clinical efficacy as the primary outcome [14]. Thus, neither study is closely similar to ours. A review article published in 2011 [7] showed that many studies supporting initial dual therapy in the most severe CAP requiring hospital admission were often retrospective, used a broad range of antibiotic regimens with some leading to conflicting results. As a result, the applicability of their results to everyday ICU practice can be challenged. In vitro resistance to macrolides has been associated with a higher clinical failure rate [33]. Despite consistent reports of increasing resistance to many antibiotics [33, 34], treatment failure remains extremely rare in patients with CAP. That β-lactams are not effective against L. pneumophila may seem to support dual therapy. However, L. pneumophila infection is rare and routinely sought by cultures or urine antigen testing (for type 1), with specific treatment being started at the slightest doubt, as this strategy has been shown to improve survival [35].

The main rationale for dual therapy is that the broader spectrum thus obtained covers atypical pathogens (other than Legionella pneumophila). However, only low-level evidence is available to support this rationale [19], as most studies were retrospective and had limited statistical power. The role for atypical pathogens in CAP has been extensively reviewed [5–7, 17, 18]. The absence of benefits from dual therapy on survival in our study may be partly due to the low frequency of atypical pathogens. A 2012 Cochrane review of randomized controlled trials in patients admitted to wards or ICUs for CAP found no benefit of atypical-pathogen coverage on clinical efficacy (the primary outcome) or survival, even in the subgroup of patients with atypical bacteria [36].

Another theoretical reason for using dual therapy is the possibility of improved effectiveness in patients with CAP due to resistant bacteria. We excluded patients with COPD and those admitted from long-term healthcare facilities, in whom repeated exposure to antibiotics increases the risk of bacterial resistance. The resulting low proportion of patients with initial bacterial resistance may have contributed to the absence of an effect of dual therapy on survival in our study.

Dual therapy might be expected to improve outcomes of patients with the most severe forms of CAP. Dual therapy was associated with better 28-day survival in patients with CAP and septic shock [3] and with better ICU survival in patients with severe CAP including 75.7% with septic shock [8]. In a retrospective study, treatment with a β-lactam and macrolide combination provided better 14-day and 30-day survival than did a fluoroquinolone alone in patients admitted for severe CAP [37]. In our study confined to ICU patients, dual therapy was not better than monotherapy, even when the second antibiotic was a macrolide. Patients with severe CAP usually undergo comprehensive investigations on an emergency basis, and their antibiotics are very quickly adapted to the microscopic smear results than to the susceptibility test results. This approach may decrease the impact of initial empirical dual antibiotic therapy.

Overuse of antibiotics, particularly fluoroquinolones [38, 39], might increase the risks of MDR bacteria selection and nosocomial pneumonia, although convincing clinical data to support these possibilities is lacking [40]. Secondary identification of MDR bacteria and nosocomial pneumonia occurred in similar proportions of patients in the monotherapy and dual therapy groups in our study. This finding should not be construed as evidence that unnecessary antibiotic use is harmless. Widespread antibiotic overuse does select MDR bacteria. Furthermore, both macrolides and fluoroquinolones can cause arrhythmias by prolonging the QT interval [41].

The strengths of our study are the large sample size, prospective data collection, patient identification based on clinical variables as opposed to codes [20], high quality of the database, and careful adjustment for confounding variables. Furthermore, to avoid including patients with healthcare-associated infections, which require specific treatment approaches, we excluded patients with immunodeficiencies, COPD or chronic dialysis as well as patients admitted from long-term healthcare facilities. The main limitation of our study is the observational design without random allocation of the initial antibiotic regimen. Randomized studies specifically evaluating β-lactam therapy alone or with a macrolide or fluoroquinolone would probably require very large sample sizes. Also, we had no information on antibiotic use in the six months preceding the CAP episode or on recent and/or repeated contact of the patients with healthcare professionals. This last factor may explain the high proportion of patients with gram-negative bacilli in our study. However, the possibility that patients with healthcare-associated pneumonia may be at increased risk of death because of their distinctive bacteriological features (including increased resistance) was challenged recently [28]. The higher mortality in these patients may be related instead to other factors, including functional impairments, malnutrition and a more restrictive ICU-admission policy. After careful adjustment for these factors, mortality was not significantly increased. Thus, there may be no sound rationale for modifying current guidelines for this particular population [28].

In conclusion, initial adequate therapy was associated with better 60-day survival in our patients with CAP requiring ICU admission and without COPD or immunodeficiency. Dual therapy (β-lactam plus macrolide or fluoroquinolone), compared to monotherapy (β-lactam alone), was associated with adequacy of initial antibiotic therapy but did not improve 60-day survival. Dual therapy did not increase the risks of nosocomial pneumonia or secondary bacterial multidrug resistance.

● Initial adequate therapy was associated with better 60-day survival in ICU patients admitted for community-acquired pneumonia.

● Dual therapy with a β-lactam plus a macrolide or fluoroquinolone, although usually recommended as better than β-lactam monotherapy in severe community-acquired pneumonia, improved the adequacy of initial antibiotic therapy but did not improve 60-day survival.

● Dual therapy with a β-lactam plus a macrolide or fluoroquinolone did not increase the risk of nosocomial pneumonia or multidrug-resistant bacteria.