This study was undertaken to evaluate the risk factors for mortality and the effect of inappropriate initial antimicrobial therapy on the outcome of patients with antibiotic-resistant gram-negative bacteremia. We found that severity of illness, septic shock, a high-risk source of bacteremia, and P. aeruginosa infection were strong prognostic factors of mortality. Inadequately treated patients had significantly higher mortality than adequately treated patients, although statistical significance was not reached by multivariate analysis after adjusting for confounding variables. The overall mortality rate was 33.2%, with rates of 27.4 and 38.4% for patients that received appropriate and inappropriate antimicrobial therapy, respectively. Thus, an 11% reduction in the overall crude mortality rate was associated with adequate early empirical antimicrobial therapy. Furthermore, for patients with a high-risk source of bacteremia, such as lung, peritoneum, or an unknown source, inappropriate initial antimicrobial therapy was identified as an independent risk factor for mortality (OR, 3.64; 95% CI, 1.13 to 110.72) after adjusting for confounding variables. Thus, the adequacy of initial antimicrobial therapy was an important determinant of survival, especially in patients with a high-risk source of bacteremia.
These results are in line with those of others who found that inappropriate empirical antimicrobial therapy of bacteremia was independently associated with higher mortality in different groups of patients (5
). Our study findings and the published literature strongly support the concept that inappropriate initial antimicrobial therapy has an adverse effect on survival in patients with gram-negative sepsis (10
In our study, it was noted that inappropriate initial antimicrobial therapy was independently associated with increased mortality in patients with a high-risk source of bacteremia, whereas inappropriate initial antimicrobial therapy was not found to be associated with increased mortality in patients with a low-risk source of bacteremia. Our study did not find a significant association between inappropriate initial antimicrobial therapy and the outcome of patients with low-risk sources of bacteremia including pancreaticobiliary tract, urinary tract, or a catheter-related source, although the 95% CI was relatively wide (OR, 1.08; 95% CI, 0.28 to 4.18) and thus likely contributed to the lack of ability to detect a significant difference. In these patients, the independent risk factors for mortality were septic shock, an increasing APACHE II score, and P. aeruginosa
infection. The lack of significant association between inappropriate initial antimicrobial therapy and the outcome of patients with a low-risk source of bacteremia may have been due to a high proportion of catheter removal or early intervention for decompression of biliary or urinary obstruction in the majority of patients. It might indicate that nonmedical interventions such as decompression of obstruction or the removal of infection foci are also important aspects of the treatment of infection. Our results suggest that when gram-negative bacteremia is suspected, the most significant prognostic variables are the primary site of infection (i.e., high-risk or low-risk site) and the severity of the underlying illness (i.e., higher APACHE II score or septic shock). Also, our data suggest that a delay in appropriate antimicrobial therapy might not lead to an adverse outcome in patients with a low-risk source of bacteremia if appropriate definitive antimicrobial therapy is administered and appropriate decompression procedures are conducted. Similarly, in our previous study of Staphylococcus aureus
bacteremia, we suggested that the effect of inappropriate antimicrobial therapy and methicillin resistance on outcome depended on the primary foci of infection (11
). The outcomes of bloodstream infections may depend on underlying conditions, the severity of illness, the adequacy of antimicrobial agents, and the primary site of infection. Also, the effect of inappropriate initial antimicrobial therapy may also depend on the severity of the underlying illness, the duration of delay in appropriate therapy, the removal of infection foci, the virulence of the microorganism, and the primary site of infection.
In the present study, no significant differences in severity of illness (as measured by the APACHE II score) or incidence of septic shock hampered the outcome comparison between the appropriate initial antimicrobial therapy group and the inappropriate therapy group. However, one possible weakness of our study is that the outcome comparison between the two patient groups may have been confounded by differences in the clinical virulence of the types of gram-negative bacteria involved. For example, P. aeruginosa isolates, which are known to be extremely virulent, were more common in the inappropriate antimicrobial therapy group. Nevertheless, by multivariate analysis including patients with a high-risk source of bacteremia, inappropriate initial antimicrobial therapy was found to be independently associated with a higher mortality.
Kollef suggested that several factors were associated with a greater likelihood of inappropriate antimicrobial therapy, namely, the presence of multiple infecting organisms, fungal infection, P. aeruginosa
infection, and antibiotic-resistant bacteria (14
). However, in the present study, cases with polymicrobial infection were distributed evenly among those treated with appropriate and inappropriate initial antibiotics, and thus, in contrast to Kollef's findings, there wasn't a higher proportion of inappropriate antimicrobial therapy in the group of patients with polymicrobial infections. Also, it may be presumed that serious infections caused by antibiotic-resistant bacteria have a worse prognosis because of the delay in initiation of appropriate antibiotic therapy (14
). In our study of antibiotic-resistant gram-negative bacteremia, we found that inappropriate initial antimicrobial therapy might adversely affect outcome. These findings suggest that continuing efforts should be directed at reducing inappropriate empirical antimicrobial therapy to septic patients, especially in cases of suspected gram-negative sepsis. Therefore, broad-spectrum cephalosporin monotherapy might not provide an optimal therapeutic option as an empirical antimicrobial regimen for the treatment of gram-negative sepsis if antibiotic-resistant gram-negative bacilli are prevalent, especially in patients with risk factors of antibiotic-resistant bacterial infection. However, empirical antibiotics for serious infections should be recommended on the basis of the distribution of pathogens and their susceptibility patterns in the institution where the regimen is administered. Furthermore, the effect of inappropriate antimicrobial therapy might depend on the severity of the underlying illness and comorbid conditions of the patients.
The main limitation of the present investigation is that it was observational and not randomized, and thus, an unknown risk factor for mortality might have been unequally distributed between the two groups. Also, we did not identify the factors that influenced the attending physician's delay in administrating appropriate antimicrobial therapy; therefore, we can't exclude the possibility of unmeasured confounding factors. However, the association between early empirical antimicrobial therapy and mortality in patients with sepsis should be investigated in an observational manner, because ethical considerations preclude a prospective randomized trial. In addition, it is unlikely that randomized controlled trials on therapy for infections due to antibiotic-resistant gram-negative bacteremia will be performed in the near future. Although the evidence of a statistical association between initial inappropriate antimicrobial therapy and mortality does not prove causality, our data suggest that mortality in inadequately treated patients can't be attributed to comorbid conditions, the severity of illness, baseline organ dysfunction, or the causative microorganisms alone.
In the present study, the analysis data set did not include very high APACHE II scores (above 25), and only 19% of patients required ICU care. Thus, the results of our study may not be applicable to the critically ill patients who require ICU care. Indeed, there is controversy regarding the impact of inappropriate initial antimicrobial therapy on the outcome of critically ill patients in the ICU setting (2
). Further investigations in a larger data set are warranted.
In conclusion, this investigation shows that administration of inappropriate initial antimicrobial therapy might be associated with an adverse outcome in those patients with antibiotic-resistant gram-negative bacteremia. In particular, in patients with a high-risk source of bacteremia such as lung, peritoneum, or an unknown source, inappropriate initial antimicrobial therapy had an independent adverse effect on the outcome of patients after adjusting for a large number of potential confounders.