Impact of empiric antibiotic therapy on outcomes in patients with Pseudomonas aeruginosa bacteremia

Osih RB, McGregor JC, Rich SE, et al. Antimicrob Agents Chemother 2007;51:839–844.

Summary:

These investigators performed a retrospective study examining the impact of appropriate antimicrobial therapy on outcomes in patients with Pseudomonas aeruginosa bacteraemia. As noted in this manuscript, P. aeruginosa bacteraemia is reported to have mortality rates between 18% and 39%. At least some of these deaths have been attributed to inappropriate initial antimicrobial therapy for this serious infection. Based on prior studies, it is reasonable to assume that early appropriate antimicrobial therapy should be associated with improved clinical outcomes for patients with P. aeruginosa bacteraemia. In fact, most studies examining this issue have found this to be the case for Gram-negative bacteraemia in general, as well as other bacterial infections, including nosocomial pneumonia, community-acquired pneumonia, Gram-positive bacteraemia and sepsis/septic shock. However, the purpose of the present analysis was to better assess the impact of inappropriate therapy on patient outcomes for the specific infection of P. aeruginosa bacteraemia. In order to do this, the authors had the following requirements in order to conduct their analysis:

1. Define the antibiotic therapy for these patients and identify what constitutes appropriate empiric antimicrobial therapy. They also wanted to strictly define the timing of antimicrobial therapy.
2. Assess the severity of the illness at a time when it would reflect the patient’s baseline severity of illness and not the consequence of the inappropriately-treated infection.
3. A large number of patients with bacteraemia caused by P. aeruginosa, in order to provide statistical robustness.

Overall, the authors were able to meet most of these requirements. However, there are several limitations in their data that preclude their results from being generalised to all patient populations.

Unexpectedly, the investigators did not find that appropriate antimicrobial therapy was associated with improved outcomes. Appropriate therapy was defined as being administered between 8 hours before culture collection and up to the time that susceptibility results became known. They also performed an additional analysis examining the relationship between timing of therapy and outcomes.

The authors found that 123 (86%) patients received appropriate antimicrobial therapy by their definition. Only 44 (14%) patients did not receive appropriate therapy. However, the mean time from culture collection to obtaining susceptibility results (their surrogate definition for appropriate therapy) was reported to be 3.4 days (range, 1–10.4 days). After adjusting for severity of illness, age and time at risk, the investigators found that appropriate therapy was not independently associated with mortality. The authors concluded that appropriate empiric therapy for P. aeruginosa bacteraemia before knowing susceptibility results may not be associated with improved outcomes.

The following limitations of the authors’ analysis restrict the overall interpretation of their data and conclusions:

1. The number of patients classified as receiving inappropriate therapy was small. This limits the ability of this variable to be identified as a predictor for outcome in the multivariate analysis.
2. The definition of appropriate or inappropriate therapy was not consistent for all patients. Patients could be classified as receiving inappropriate therapy if they were identified at the time susceptibility results became known, 24 hours following cultures or as late as 10.4 days following cultures. Too many studies have identified timing of therapy as being a critical determinant of outcome for patients with severe infections. Therefore, the variability in how appropriate therapy was determined for each patient is an important limitation of these data.
3. In a bivariate analysis, the authors’ data show trends suggesting that appropriate antimicrobial therapy was associated with better outcomes, regardless of the timing used to define appropriate therapy in relation to culture results. This supports the contention that a lack of power and inconsistent timing criteria were not appropriate for this study.
4. The authors did not examine the relationship between the antimicrobial regimen prescribed ‘initially’ and its association with outcome. Many other studies have considered this initial antimicrobial therapy to be the most important timepoint for outcome analysis.

AIM Core Principles Supported:

Several principles proposed by AIM are supported in the current paper, with particular focus on the following principles:

Patient outcomes

• Antibiotic choice: empiric antibiotic regimens should be designed to cover the likely pathogens initially. This is at the heart of most published guidelines, including the ATS/IDSA guidelines for community-acquired (Mandell et al. Clin Infect Dis 2007;44:S27–S72) and nosocomial pneumonia (ATS/IDSA. Am J Respir Crit Care Med 2005;171:388–416). Guidelines make recommendations based on the underlying pathogens associated with infection, which are centred on patient risk factor profiles for infection with potentially antibiotic-resistant bacteria.
• Antibiotic choice: it is important to start with the appropriate empiric antibiotic first in nosocomial infections. The results of the present analysis do not emphasise that getting it right the first time is a key component of therapy.
• Patient outcomes: select the most appropriate antibiotic depending on the patient, risk factors, suspected infection and local patterns of antimicrobial resistance. Clinicians should not wait until susceptibility results are known to administer appropriate therapy to the patient. This is especially true when rapid susceptibility results cannot be obtained.

Learning points:

• Early appropriate antimicrobial therapy has been shown to be an important determinant of outcome in most studies examining this variable. Importantly, in serious infections, such as P. aeruginosa bacteraemia, clinicians should strive to prescribe initial antimicrobial regimens that will be appropriate for this pathogen.