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Antibiotic Therapy and Outcome in Critically Ill Patients with Pneumococcal Bacteremia

With considerable interest we have read the article by Baddour and colleagues suggesting that combination antibiotic therapy improves outcome in critically ill patients with pneumococcal bacteremia (1). While this prospective study adds support to a previous retrospective observation, some concerns are raised. Empiric combination therapy with a -lactam together with a macrolide or a fluoroquinolone was only prescribed in 14 and 4 patients, respectively, out of a total of 94 critically ill patients, suggesting that treatment guidelines for severe community-acquired pneumonia still are followed poorly. It is remarkable that the survival advantage associated with combination therapy was only observed in the subgroup of critically ill patients. Evidence has been accumulating that the progression of uncomplicated infection to severe sepsis and multiple organ failure is not only determined by virulence of the causative agent, but is also strongly linked with host response factors, such as activation of the inflammatory and coagulation cascade (2, 3). This is corroborated by the survival benefit observed in patients receiving activated protein C (4).

A microbiological or clinical rationale to explain the survival advantage associated with combination antibiotic therapy still is lacking after the study by Baddour and coworkers (1). Whereas timely institution of appropriate antibiotic therapy is known to be an important prognostic factor both in community-acquired and nosocomial infection, this cannot explain the survival benefit of the current study, as the antibiotic therapy reported was highly heterogeneous but active in vitro (at least for one component). This absence of rationale should caution against hypotheses raised by statistical findings. As can be seen in Table 2 of Baddour and coworkers' article, adjustment for mechanical ventilation in bivariate analysis reduced the level of significance from 0.0015 to 0.04. It would be interesting to know whether the survival advantage associated with combination antibiotic therapy still would be significant when adjusted for other factors which are known to be related with outcome in critically ill patients, such as severity of illness, comorbidity and community-acquired versus nosocomial infection, nonantibiotic treatment such as activated protein C, early goal-directed therapy and corticosteroids (5). To avoid missing significant associations in multivariable analysis, it has been recommended to include all variables which have a theoretical or a priori probable association with the response variable, as well as all variables having a p < 0.25 association in univariate analysis (6). In conclusion, the superiority of combination antibiotic therapy in the treatment of pneumococcal bacteremia can only be proven in a randomized controlled trial.

P. Depuydt, D. Benoit, K. Vandewoude and J. Decruyenaere

Ghent University Hospital, Ghent, Belgium

FOOTNOTES

Conflict of Interest Statement: P.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. Baddour LM, Yu VL, Klugman KP, Feldman C, Ortqvist A, Rello J, Morris AJ, Luna CM, Snydman DR, Ko WC, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004;170:440–444.[Abstract/Free Full Text]
2. Ioanas M, Ferrer M, Cavalcanti M, Ferrer R, Ewig S, Filella X, de la Bellacasa JP, Torres A. Causes and predictors of nonresponse to treatment of intensive-care unit-acquired pneumonia. Crit Care Med 2004;32:938–945.[CrossRef][Medline]
3. Quasney MW, Waterer GW, Dahmer MK, Kron GK, Zhang Q, Kessler LA, Wunderink RG. Association between surfactant protein B 1580 polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia. Crit Care Med 2004;32:1115–1119.[CrossRef][Medline]
4. Bernard GR, Vincent JL, Laterre P, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.[Abstract/Free Full Text]
5. Vincent JL, Abraham E, Annane D, Bernard G, Rivers E, Van den Berghe G. Reducing mortality in sepsis: new directions. Crit Care 2002;6:S1–S18.
6. Hosmer DW, Lemeshow S. Applied logistic regression, 2nd ed. New York: Wiley Interscience; 2000.

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