Despite numerious studies in the literature, most of our knowledge about the risk factors and prognostic impact of inadequate initial AB was based on studies of VAP because well-conducted studies involving patients who are not undergoing mechanical ventilation are lacking. Similarly the American Thoracic Society/Infectious Diseases Society of America evidence-based guidelines for nosocomial pneumonia are mainly based on studies of VAP but it is recommended to treat patients who were not intubated or undergoing mechanical ventilation, in the same manner as those with VAP . Although treatment alternatives are similar, in our study we planned to evaluate the risk factors for inadequate initial AB and the impact of adequacy of initial AB on the prognosis of patients with HAP and VAP separately.
In this study 66.6% of patients in VAP and 41.3% of patients in HAP received inadequate initial AB. The percentage of patients who received inadequate initial AB is quite variable in the previously published studies and changes from 10% to 73% [8–11, 13–18]. The knowledge regarding the colonization of patients, the need to limit selection pressure and the sensitivity profile of the suspected pathogens may influence the frequency of inappropriateness of initial AB.
We identified higher APACHE II score and late-onset pneumonia as independent risk factors for inadequate initial AB for patients with HAP. Although severity indices are not always mentioned in studies regarding the adequacy of AB of pneumonia, patients with higher severity are considered to be at high risk of poor outcome and they are also likely to be infected by more resistant bacteria [10, 11]. Similarly late-onset nosocomial pneumonia is caused most frequently by hospital-acquired and often MDR pathogens [20–22]. The potential involvement of more resistant bacteria in the late-onset pneumonia is more likely to lead to inadequate treatment with traditional antibiotic regimens [4, 6, 8, 22]. However, we did not find such association in late onset pneumonia regarding the adequacy of initial AB and susceptibility patterns of the isolated pathogens when we performed the analysis in culture positive patients only. This conflicting result may be explained by the distribution of MDR bacteria within the groups. In our study cohort the presence of MDR bacteria was higher in the inadequate treatment arm in HAP patients and this was statistically significant. But this significance could not be shown when only culture positive HAP patients were analyzed. So we may conclude that the causative pathogens in late-onset pneumonia in culture negative HAP patients were resistant to the initial empiric AB. Although the presence of polymicrobial etiology were found to be associated with inadequate initial AB in HAP patients both in general and in the subgroup analysis of the culture positive patients, it was not determined as an independent risk factor. We believe that this may be due to the small number of patients with polimicrobial etiology.
For patients with VAP previous antibiotic usage and admission to a surgical unit were found to be independent risk factors for inadequate AB. Previous antibiotic exposure is one of the most evident risk factors for nosocomial infections due to antibiotic-resistant bacteria, and it was reported as an independent risk factor for inadequate AB in most of the previously published studies [6, 10, 22–24]. “Admission to a surgical ICU” as being a risk factor for inadequate AB is more difficult to explain. The separation of patients into medical and surgical units without identifying the performed surgical procedure may have affected the analysis of risk factors.
In our study cohort, all of the identified risk factors were shown to be indirectly associated with the acquisition of resistant bacteria for both VAP and HAP. However, in contrast to the results of other previously published studies, multivariate analysis showed that, presence of MDR bacteria was not an independent risk factor for both of the groups, [5, 8]. This contradictory finding may be due to the MDR Acinetobacter spp. outbreak which had just begun early in the study period in our ICUs. This could also be a possible explanation of high rates of inadequate therapy in our study population in general. We reevaluated the empiric treatment choices after the antibiotic susceptibility profile of the epidemic clone had been identified. For some of the isolates colistin was the only drug of choice but since colistin was unavailable in the market, in Turkey at the time of the study, we were not able to use it as an empirical treatment option. As a result the presence of MDR bacteria was high in both of the treatment groups and the difference regarding the frequency of MDR bacteria between groups did not reach statistical significance. In patients with HAP, presence of MDR bacteria was associated with inadequate AB but in the final multivariate model this was not significant. Although we have included both culture positive and culture negative patients in the risk factor analysis, the impact of presence of MDR bacteria did not change when the analysis was performed in culture proven patients only.
In this study, we were not able to find any statistically significant difference in mortality rates between patients who received inadequate initial AB and patients who received adequate initial AB for both HAP and VAP. Available studies evaluating the impact of empirical AB have produced conflicting results; some found positive correlation between adequate empirical AB and survival, whereas others did not [8–15]. These contradictory results are probably ascribable to differences in patients and pathogens responsible for pneumonia; since in the studies those found higher mortality rates when AB was inadequate, the patients who received inadequate AB were the ones with pneumonia caused by the most difficult to treat microorganisms [5, 11]. In a prospective study of patients with late-onset VAP; it was reported that infection due to non-fermenting gram-negative bacilli was the most important predictor of in-hospital mortality . These pathogens were also the most common isolates in our study. However, the frequency of non-fermenting gram-negative bacilli in the inadequate and adequate AB groups was not significantly different and this may have affected the survival results. Another reason may be the difference in the definition of adequate AB as in some studies adequate AB was defined as AB with a favorable clinical response and in others it is described as microbiological recovery of susceptible organisms to the empirical antibiotic regimen. In the present study we used both of these definitions; in culture positive patients the adequacy of antibiotics were defined according to the results of the antimicrobial susceptibility testing whereas in culture negative patients clinical response to the empiric antibiotic regimen was taken into consideration. However the assosciation between the adequacy of the initial AB and survival did not change when the analysis was performed in culture positive patients only for both VAP and HAP.
In our study cohort although we could not find a positive correlation between adequate initial antimicrobial therapy and survival, we showed a significant increase in ICU length of stay, duration of mechanical ventilation and a prolonged clinical resolution in the inadequate AB group for both VAP and HAP. Other researchers also reported an increased length of stay and increased duration of mechanical ventilation when initial AB was inadequate in comparison with adequate AB [6, 10]. Only in one study evaluating the outcome of patients with VAP, length of ICU and hospital stays were found to be similar in patients who did and did not receive adequate initial AB . For patients receiving adequate AB, it was reported that clinical resolution of pneumonia usually begins during the first several days of treatment [6, 25]. Our results were correlated with the literature, besides we showed a significant prolongation of the clinical resolution when the initial antibiotic therapy was inadequate.
The present study has several limitations. Its retrospective design is a limitation, since it was not possible to conduct an accurate analysis of any changes in the empirical AB regimens. On the other hand, the retrospective feature could have been an advantage as the prescription of initial AB was not influenced by a prospective evaluation during which a large spectrum initial AB could have been chosen. Another limitation is the impact of specific pathogens on the adequacy of initial AB and survival could not be performed because stratification into smaller groups would complicate entry in the logistic regression model, as each group would have a very small number of cases.