Fever, Neutropenia, and the Second Law of Thermodynamics

The management of the patient with cancer who has chemotherapy-induced neutropenia and fever has changed markedly over the past four decades. Empirical antimicrobial therapy is now the standard of care for any patient with cancer and neutropenia who has unexplained fever, rigors, or subtler signs of sepsis (for example, unexplained tachypnea, volume requirement, or acidosis). Although different organisms have been found in these patients over time (Enterobacteriaceae and Pseudomonas aeruginosa through the 1980s, and now mostly gram-positive organisms), empirical therapy has been validated by several well-designed comparative trials, including studies conducted by the European Organisation for Research and Treatment of Cancer, the National Institutes of Health, and numerous academic medical centers (1). The study by Peacock and colleagues in this issue (2) adds significantly to our understanding of the effect of this approach in desperately ill patients with cancer.

What have we learned from this effort? First, temporal factors are important. Whereas gram-positive bloodstream infections must be treated, immediate initiation of vancomycin therapy is not essential unless the patient is already in extremis. Thus, gram-positive therapy can be delayed until an invasive gram-positive infection is identified on culture or by careful examination of the patient in question (3). Gram-negative coverage, in contrast, must begin immediately because the patient will otherwise be at risk for gram-negative sepsis, which can progress rapidly in persons with neutropenia.

Second, there is a logical sequence in which antimicrobial agents ought to be prescribed: Broad-spectrum anti–gram-negative therapy should be started immediately, and antifungal therapy should be used 72 to 96 hours later if the patient has not responded. Vancomycin should be added to the regimen if culture or physical examination reveals a gram-positive infection or if the empirical anti–gram-negative therapy has limited coverage of …