Imipenem

To the Editor:

Baddour and colleagues' prospective study design and large numbers of subjects help to confirm that treatment of bacteremic pneumococcal pneumonia with two drugs is associated with improved survival as compared with single drug therapy (1). Previous studies showed similar results (2-4). The consistency of these findings suggests that the association between combination therapy and improved survival is causal. However, the mechanism(s) by which such benefit is derived is unknown. Baddour and colleagues help to clarify this issue by confirming that this survival benefit is not dependent on inclusion of a macrolide in combination regimens (3), and by showing that the reduction in mortality occurred exclusively among the 94 critically ill patients (14-d mortality rates of 23.4% and 55.3% among critically ill recipients of two- and one-drug therapy, respectively, p = 0.0015), with no discernible difference in mortality among the 498 patients who were less ill (1). Thus, it seems that either a second antibiotic, irrespective of the agent used, confers added survival benefit only with critical illness, or single-drug therapy somehow becomes less effective in that context.

There is conflicting evidence in favor of the former, "value-added" hypothesis. After assigning each of the 201 patients in their retrospective series a predicted risk of mortality based on APACHE II scores, Waterer and coworkers (3) found that the observed mortality among single-antibiotic recipients was similar to the predicted mortality, whereas the observed mortality for two-drug recipients was nearly 10% lower than predicted (6.9% and 16.4%, respectively), suggesting that the addition of a second drug was responsible for the differences in mortality. By contrast, the high mortality rate of the critically ill recipients of one-drug therapy reported by Baddour and colleagues (26 [55.3%] of 47) (1) seems more consistent with a loss of effectiveness of single-drug therapy in this setting.

Altered antibiotic pharmacokinetics during critical illness may explain why an otherwise effective single-drug regimen might fail in critical illness. Reductions in scrum proteins, especially albumin, and an expanded volume of distribution may hasten drug clearance so long as excretory-renal and/or hepatic-function remains intact (5). This has been shown to occur with ceftriaxone. a third-generation cephalosporin commonly used to treat community-acquired pneumonia, whose prolonged elimination half-life in normal subjects-approximately 8 h-depends upon extensive protein binding. Joynt and colleagues (6) found that free ceftriaxone levels fell to undetectable levels within 8 h of dosing in all eight critically ill adults with normal renal function given ceftriaxone 2 g daily. Since the unbound moiety of ceftriaxone and other protein-bound antibiotics is presumed to be responsible for bacterial killing, and because, as with other β-lactam antibiotics, free ceftriaxone levels must exceed the minimum inhibitory concentration of the infecting pathogen for at least 40% of the dosing interval-9.6 h when dosed every 24 h-to cure bacterial infections reliably, clinical failure is predictable under these circumstances (6). Indeed, once-daily ceftriaxone was found to be inferior to cefotaxime in a comparative trial involving 51 critically ill patients with pneumonia despite the virtually identical antimicrobial spectra and potency of the two drugs (7). On the basis of these considerations, we have recommended that critically ill adults with normal renal function in our institution he given ceftriaxone as 1 g every 12 h.

Ceftriaxone was likely to have been given to many single-antibiotic recipients in the studies showing improved survival for combination therapy in bacteremic pneumococcal pneumonia: 25 (53%) of 47 reported by Baddour and colleagues (1), 25 (25%) of 99 described by Waterer and colleagues (3), and 106 (62%) of 171 reported by Martinez, and colleagues (4) received unspecified third-generation cephalosporins. Did the specific antibiotic type correlate with survival in these studies, especially after stratifying for the presence of critical illness as performed by Baddour and colleagues (1)?

Highly variable and often inadequate pharmacokinetic parameters have been described for antibiotics other than ceftriaxone in critical illness (8, 9). Thus, dosing antibiotics to better account for such variations may be necessary to reap their full benefits in the intensive care unit (10).

Conflict of Interest Statement: D.N.S. 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.

2. Mufson MA, Stanek RJ. Bacteremic pneumococcal pneumonia in one American city: a 20-year longitudinal study, 1978-1997. Am J Med 1999;107:34S-43S.

3. Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med 2001;161:1837-1842.

4. Martinez JA, Horcajada JP, Almela M, Marco F, Soriano A, García E, Marco MA, Torres A, Mensa J. Addition of a macrolide to a β-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2003;36:389-395.

5. van Dalen R, Vree TB. Pharmacokinelics of antibiotics in critically ill patients. Intensive Care Med 1990;16:S235-S238.

6. Joynt GM, Lipman J, Gomersall CD, Yound RJ, Wong ELY, Gin T. The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. J Antimicrob Chemother 2001;47:421-429.

7. Reeves JH, Russell GM, Cade JF, McDonald M. Comparison of ceftriaxone with cefotaxime in serious chest infections. Chest 1989;96:1292-1297.

8. Lipman J, Wallis SC, Rickard CM, Fraenkel D. Low cefpirome levels during twice daily dosing in critically ill septic patients: pharmacokinetic modeling calls for frequent dosing. Intensive Care Med 2001; 27:363-370.

9. Belzberg H, Zhu J, Cornwall EE, Murray JA, Sava J, Salim A, Velmahos GC, Gill MA. Imipenem levels are not predictable in the critically ill patient. J Trauma 2004;56:111-117.

10. Mohr JF, Wanger A, Rex JH. Pharmacokinetic/pharmacodynamic modeling can help guide targeted antimicrobial therapy for nosocomial gram-negative infections in critically ill patients. Diagn Microbiol Infect Dis 2004;48:125-130.

DAVID N. SCHWARTZ

Stroger Hospital of Cook County

Chicago, Illinois

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