Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis

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Abstract

Purpose

To examine the effect of inappropriate initial antimicrobial therapy on the prognosis of patients with sepsis who were enrolled in a clinical trial of an immunomodulating agent conducted in 108 hospitals in North America and Europe.

Methods

We assessed initial antimicrobial choice and results of microbiologic cultures in 904 patients who had microbiologically confirmed severe sepsis or early septic shock. If a patient did not receive at least one antimicrobial agent to which the causative microorganisms were susceptible within 24 hours from the diagnosis of severe sepsis, then the initial antimicrobial treatment was considered to be inappropriate. A propensity score that adjusted for factors associated with inappropriate antimicrobial treatment was calculated and included in multivariable models to adjust for confounding.

Results

A total of 468 patients (52%) had documented bloodstream infection, and 211 patients (23%) received inappropriate initial antimicrobial therapy. Characteristics associated with inappropriate treatment were study enrollment in Europe, admission to surgery, nosocomial infection, infection with multiresistant microorganisms, and fungal or polymicrobial infection (all P <0.05). The 28-day mortality was 24% (168/693) for patients in the adequately treated group versus 39% (82/211) for patients receiving inappropriate initial antimicrobial therapy (P <0.001). After adjusting for comorbid conditions, severity of illness, site of infection, and the propensity score, inappropriate antimicrobial therapy was independently associated with increased mortality (odds ratio = 1.8; 95% confidence interval: 1.2 to 2.6).

Conclusion

In a large cohort of patients with microbiologically confirmed severe sepsis, appropriate initial antimicrobial therapy was an important determinant of survival. New approaches aimed at improving detection and treatment of early sepsis are needed.

Section snippets

Study sample

We used a multicenter database of 1342 patients (aged >18 years) with severe sepsis or early septic shock who were enrolled in a double-blind, placebo-controlled phase 3 trial of the safety and efficacy of lenercept (p55 immunoglobulin G tumor necrosis factor receptor fusion protein) (20). The study was conducted in 108 community and university-affiliated hospitals in the United States (n = 60), Canada (n = 6), and Europe (n = 42). Overall, there was no difference in 28-day mortality between

Results

Of the 1342 patients, 904 (67%) had microbiologically documented severe sepsis or early septic shock and were included in the study. The mean (± SD) patient age was 60 ± 17 years; 548 patients (61%) were male. The mean SAPS II–predicted 28-day mortality was 34% ± 19%. There was no baseline organ dysfunction in 204 patients (23%), whereas 410 patients (45%) had dysfunction of one organ, 209 (23%) had dysfunction of two organs, and 81 (9%) had dysfunction of three or more organs. Respiratory

Discussion

This study evaluated the effect of inadequate initial antimicrobial treatment on outcome in critically ill patients with microbiologically documented severe sepsis or early septic shock. We found that both the severity of illness and the number of organ dysfunctions at baseline proved to be strong prognostic indicators of mortality. After adjusting for confounding, inappropriate antimicrobial treatment was associated with increased mortality. Thus, adequacy of antimicrobial therapy was an

Acknowledgements

We are grateful to the many investigators and staff who were involved in enrolling patients in this clinical trial and whose detailed record-keeping enabled the analysis reported here. In particular, we would like to thank the other members of the Geneva Sepsis Network (J. C. Chevrolet, J. M. Dayer, P. Eggimann, T. Fumeaux, B. Ricou, and P. Suter) for their help and collaboration.

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  • The original clinical trial was supported by Hoffmann-La Roche Ltd., Basel, Switzerland. The sponsor had no role in data analysis or in the submission of this report.

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