Improvement of antibiotic therapy and ICU survival in severe non-pneumococcal community-acquired pneumonia: a matched case–control study

The most relevant conclusions of the present analysis were the significant decrease in ICU mortality due to non-pneumococcal SCAP between the two cohorts, and the positive association between improved empirical antibiotic treatment and a lower mortality rate. These findings confirm our primary hypothesis, and are consistent with the results obtained from our previous study in patients with pneumococcal CAP from the same database [9].

Few published studies have assessed changes in mortality due to CAP in recent years. Moreover, as mentioned above, the vast majority did not differentiate between critical and non-critical patients [3, 4]. However, several studies have reported a significant decrease in mortality due to all-source septic shock in recent decades [5‐7]. Our results were obtained in a population with a high rate of IMV (73.6 %) or secondary shock (59.7 %). In this setting, during the planning of a study, we believe that is vital to differentiate between critical and non-critical patients.

To our knowledge, no studies to date have assessed mortality due to SCAP with regard to etiology. It is worth noting that, during the matching process, we did not set a percentage for each microorganism a priori; instead, we found the number of coincidences between groups according to the above-mentioned variables. Interestingly, the distribution of the identified microorganisms in our sample coincides with literature reports, thus confirming the study’s external reproducibility [1, 17].

As indicated in Table 6, the vast majority of patients received adequate treatment according to microbiology. As expected, appropriateness of treatment in case of infection due to Legionella pneumophila and Pseudomonas aeruginosa was lower. In case of Legionella infection the treatment was adequate in 86.7 % of patients from the CAPUCI I and II groups. On the other hand, treatment was adequate with respect to microbiology respectively in 45.5 and 54.5 % of patients with infection due to Pseudomonas aeruginosa. This is important because an inappropriate treatment can lead to an increased mortality. In fact, the survival rate in case of Pseudomonas pneumonia was the lowest when compared with other etiologies (with the exception of Enterobacter infection; however, this is not significant as only four patients were introduced in the analysis, two in each group), and this is probably due to the low rate of adequate empirical treatment. Despite this, an improvement in mortality was observed between the two periods, and this is probably due to the earlier administration of the first dose of antibiotic and other general improvements that have been made in the last years in the management of ICU patients.

When exploring mortality depending on the etiology of pneumonia, we observed an increased survival between the two cohorts when pneumonia was caused by Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Escherichia coli and Enterobacter aerogenes. No changes were observed in case of Klebsiella infection, and an increased mortality was observed in case of Legionella pneumonia. As shown in Table 3, a higher proportion of patients from CAPUCI II received early combination therapy. When exploring the administration of mono- versus combination therapy, differentiating by the microorganisms, it becomes evident that all cases with the exception of Legionella and Pseudomonas infections received a higher rate of combined therapy if belonging to the CAPUCI II group (Table 6). Thus, it is reasonable to assume that the decrease in mortality in our sample was mainly caused by a higher rate of combination therapy and early antibiotic administration.

In the case of pneumonia due to Legionella pneumophila, an increased mortality between the two groups was observed. Fifteen patients with Legionella infection were included in both groups: 3 out of 15 and 5 out 15 died, respectively, in the CAPUCI I and II groups. Among those who died, two individuals out of three from the CAPUCI I cohort received microbiological adequate coverture (one received a quinolone regimen while the other a macrolide regimen); in CAPUCI II, they were three out of five (all received a macrolide regimen) (Table 6). On the other hand, all patients but one (belonging to the CAPUCI II group) received delayed antibiotic treatment. We assume that the small size of the sample, fortuity and probably some unrecognized factor other than antibiotic therapy played a role in the different mortality. Due to the low number of patients that died because of Legionella infection, it is difficult to ascribe changes in mortality because of the use of quinolones rather than macrolides, although it is not possible to exclude it.

Another important finding is the association between lower mortality and an improvement in antibiotic strategies; that is, combined antibiotic therapy and early treatment initiation. Combined therapy has become common practice in the empirical treatment of SCAP [1]. To our knowledge, no current guideline suggests monotherapy as empirical therapy. Generally, the recommendation is a beta-lactam plus either a macrolide or a quinolone. In the CAPUCI I group, monotherapy was administered in 17 patients (23.6 %) and in 7 patients (9.7 %) in the CAPUCI II group.

Univariate and multivariate analysis, and Kaplan-Meier survival analysis, all showed a positive association between delivery of combined antibiotic therapy and lower mortality. Previous studies observed that patients with CAP and secondary shock or bacteremia [18, 19] presented lower mortality when combined therapy was delivered. Our results confirm these findings and, furthermore, suggest that all patients with severe pneumonia, with or without shock or need for IMV, may benefit from combined therapy. Even though this may not be a surprising conclusion, it should be noted that a significant percentage of our population and those in other studies still received monotherapy [20]. These findings are consistent with those reported in patients with pneumococcal SCAP [9].

To date, the optimal antibiotic combination choice in severe CAP is still a debated issue; some authors advocate the use of a macrolide-regimen administration, due to the anti-inflammatory effects shown by these molecules [21]. However, not all studies achieved similar results. Although in our cohort the limited size of the sample makes it difficult to explore this issue, we assessed changes in mortality after macrolide or quinolone administration, in the whole population (Table 7) and in the subgroups of patients with shock or under mechanical ventilation (data not shown)—no differences were observed. Furthermore, several studies concluded that quinolone administration is comparable in terms of mortality with a macrolide regimen, but with a higher eradication rate, a lower treatment failure and possibly less cost of treatment [22]; however, concerns about an increased resistance rate after quinolone administration were raised [23]. Moreover, in case of a social environment with high rates of pulmonary tuberculosis, the use of a fluoroquinolone could mask a pulmonary tuberculosis rather than bacterial CAP [24]. In our sample, the use of a quinolone regimen showed a trend to lower mortality, without achieving significant results, in the whole population and in the subgroups of patients with shock or under mechanical ventilation. According to the present results, it is not possible to advocate the use of a specific antibiotic family.

In 2006, Kumar et al. showed that mortality rates in septic patients with shock increased in line with the delay in antibiotic initiation [25]. Subsequent other studies of patients with shock confirmed this finding [26]. As shown in the Kaplan-Meier survival analysis (Fig. 5), early antibiotic treatment in our sample was associated with lower mortality not only in the subgroup of patients with shock, but in the overall population and in the subgroup of ventilated patients as well. In view of these findings, each patient who presents at the emergency room with non-pneumococcal SCAP should receive the first dose of antibiotic treatment within the first 3 hours. Indeed, the 2007 IDSA/ATS guidelines recommend initiation of antibiotic therapy before transfer to the ward or to the ICU [1].

We explored if the agreement with the 2007 IDSA/ATS guidelines was associated with different outcomes, and we found a reduced mortality when guideline recommendations were followed. Basically, IDSA/ATS guidelines recommend the administration of an early combination of specific antibiotic families; thus, to better investigate the effects of simple medical actions on mortality, we decided to separate the item “2007 IDSA/ATS adequate treatment” into two variables: “combined therapy” and “early antibiotic treatment”. Thus, after the addition of these two variables in the multivariate model this association was no longer documented. This might suggest that the sum of actions that imply the agreement to international guidelines is better investigated by separating these actions in multiple variables rather that grouping all actions into the variable “2007 IDSA/ATS adequate treatment”.

The current study has some limitations that should be mentioned. The most important is its observational nature; however, this approach is the only way to assess changes in outcome over a period of time. Moreover, in the ICU setting in recent decades there have been significant improvements in the management of patients undergoing IMV or resuscitation of septic shock, and in nutrition, in the prevention of ICU-related complications and in the ICU admission criteria as well. Severity-of-illness was recorded with different scores; in CAPUCI I the risk of mortality was estimated using APACHE II score while in CAPUCI II SAPS III was used. However, both scales reflect a reliable risk of death and were widely validated in large-scale studies. For this, after estimating the risk of death with APACHE II and SAPS III scores, we created a variable named “estimated probability of death”, comparing both groups. Furthermore, to avoid an overlap between the same parameters in different variables, we decided not to use severity-score variables to match patients; in fact, both APACHE II and SAPS III scores include parameters of severity for respiratory or cardiac failure, and demographics such as age, which were introduced independently in the matching. Of note, the ICUs that participated in CAPUCI I and II studies were different; in fact, CAPUCI I was developed in 33 Spanish ICUs while CAPUCI II was carried out in 29 ICUs–24 from Spain and 5 from other European countries. This may originate a bias due to a different source of patients; however, after the matching process, we retrospectively observed that all 72 patients from the CAPUCI II cohort were enrolled from Spanish ICUs, thus minimizing the risk of a significant bias. Moreover, we did not perform genetic investigations, although recent publications have identified common variants in specific genes that are associated with different outcomes in severe pneumonia [27]. Finally, as stated by Waterer [28], ICU outcome often differs from hospital outcome or from outcome on day 60 or 90 after admission. However, as shown in the Kaplan-Meier survival analysis, the majority of deaths in our sample occurred within 14 days of admission. Although it is true that ICU mortality may differ from hospital or 3-month outcome, we feel that deferring excessively the time of the study of the outcome may complicate the analysis, because more variables that are difficult to record and interpret have to be introduced in the analysis as confounding variables.