In the current cohort of patients with sepsis due to Acinetobacter spp., the prevalence of carbapenem resistance was high at nearly 60%. More importantly, the risk for receiving non-IAAT in this setting was extreme. Specifically, the presence of CRAc as the infectious pathogen more than doubled the risk of receiving non-IAAT compared to having a carbapanem-susceptible isolate. Additionally, despite the high baseline rate of death in patients with Acinetobacter spp. sepsis, failure to receive appropriate therapy further increased the risk of hospital mortality.

A vast volume of research has emphasized the importance of early appropriate antimicrobial therapy in the setting of serious infections. Indeed, it has been shown in sepsis and pneumonia that the penalty for the wrong choice of empiric treatment is a 2-4-fold increase in the risk of death [6]-[8],[10]-[14], and that escalation of treatment in response to culture results fails to mitigate this increase in risk [9]. Our findings generally confirm this relationship. However, the current study adds to these earlier analyses by focusing specifically on a pathogen that is generally only sporadically found in US ICUs. The majority of earlier studies dealing with inappropriate therapy has addressed specific disease states (e.g., pneumonia), irrespective of the pathogen, or has not attempted to measure impact of inappropriate therapy in the setting of sepsis and septic shock as a syndrome. In this vein, few earlier efforts have dealt specifically with the issue of Acinetobacter spp. as a cause of bacteremia, and no other to the best of our knowledge has examined severe sepsis/septic shock. Indeed, the data on whether non-IAAT in the setting of Acinetobacter bacteremia as a contributor to the increase in the risk of death are conflicting. A small multi-center retrospective matched cohort study from Korea reported that non-IAAT was associated with a 6-fold increase in 30-day mortality [19]. Similarly, a single-center study from Turkey reported a nearly identical risk of 30-day morality to ours in association with non-IAAT (hazard ratio 2.1, 95% CI 1.2-3.7; P = 0.007) [20]. In contrast, several other studies failed to detect this relationship, though each suffered from a small sample size of bacteremia cases and other methodologic issues [21]-[24]. A cohort study from Turkey examining 100 cases of Acinetobacter bacteremia reported that carbapenem resistance was an independent risk factor for 14-day mortality [25]. However, while inappropriate empiric treatment was associated with an increase in mortality in the univariate analysis, it was not reported to be so in a multivariate analysis. It is unclear whether it was included in such and fell out or whether it was simply not examined. In either case, since we have demonstrated strong collinearity of non-IAAT with carbapanem resistance, including both in a single regression would not be statistically desirable. Another small cohort study conducted in the US examining the relationship between carbapenem resistance and mortality in A. baumanii bacteremia failed to detect an association, although appropriateness of treatment was an important determinant of hospital death [26]. However, such strong collinearity between non-IAAT and CRAc as we have detected in our study suggests that they may exist in the same causal pathway vis-à-vis outcomes. For this reason, it may be more statistically valid to examine them separately, as we have done, rather than in the same model.

Importantly, none of the above studies focused on the syndrome of sepsis. Because of the populations addressed in and limitations of earlier reports, ours expands upon past research exploring the mortality burden specifically related to Acinetobacter spp. severe sepsis and septic shock. Significantly, we illustrate that although outcomes are generally poor in persons infected with this organism, the additional impact of inappropriate therapy is substantial. As such, this suggests that there is an urgent need for agents that can provide empiric coverage for this pathogen. This last point is even more crucial in that the prevalence of drug-resistant Acinetobacter spp. is increasing both in the US and across the globe [27]. Thus, what may currently be of only a limited burden may in the future become much more of an issue. Conversely, our results emphasize the importance of public policy tools that foster drug development, such as the GAIN act, as well as the Food and Drug Administration’s attention to streamlining the development of antibacterial therapies in the setting of unmet medical needs [28].

Our results further suggest that carbapenem resistance is an important risk factor for receiving inappropriate empiric coverage. In other words, the key issue may not only be rapid identification of subjects specifically at risk for Acinetobacter spp., but may in fact be determining whether a patient is suffering from a potentially carbapenem-resistant pathogen. This not only highlights the urgent need for concerted efforts at preventing individual infections and curtailing the development and spread of resistant organisms, but also underscores the needs for novel rapid diagnostic tools. Moreover, these new diagnostics must provide clinicians up front with information about a pathogen’s likely susceptibilities rather than just simply identifying the organism.

Our study has a number of limitations. As a retrospective cohort it is prone to several forms of bias, most notably selection bias. We attempted to mitigate this by enrolling consecutive patients fitting the pre-determined enrollment criteria. Although we dealt with confounders by adjusting for those that were available, it is possible that some residual confounding remains, particularly confounding by indication. The fact that this is a single-center study in a very specific population of patients (those with Acinetobacter spp. sepsis) may diminish the generalizability of our results to other centers and populations. An additional potential threat to the generalizability of the findings is the fact that non-susceptibility to carbapanems was based on the corresponding year’s CLSI threshold for resistance. Applying higher MIC cut-offs either for carbapenems or other agents that have shown at least some in vitro susceptibilities at higher MICs would have reclassified some of the non-IAAT patients into the IAAT category [29],[30]. This reclassification would have the potential either to strengthen or to weaken the association between non-IAAT and mortality. It is important to note that, although our results strongly suggest that the association of carbapenem resistance with an increased risk of death is mechanistically related to the risk of receiving inappropriate empiric therapy, we cannot rule out that resistant Acinetobacter spp. may exert its lethal effect directly by virtue of higher virulence, as has been noted with other pathogens exhibiting higher MICs to certain antimicrobials [31],[32]. Because we examined hospital mortality rather than the more standard 28-day mortality as the primary outcome for our study, we may have underestimated the magnitude of this outcome.