The prophylaxis of bacterial infections in neutropenic patients.

Bacterial sepsis remains a major cause of morbidity and mortality in patients rendered neutropenic following cyto- reductive therapy for haematological malignancy. The introduction of more aggressive anti-neoplastic chemo- therapeutic regimes in individuals with solid organ malig- nancies has resulted in increasing numbers of these patients experiencing the profound neutropenia (i.e. granulocyte counts of 0.1 10 9 /L) that puts them at risk of infection. It is now over 30 years since Bodey et al. , in a landmark paper, 1 first quantified the risk of infection associated with severe neutropenia. Throughout this period much effort and considerable economic resources have been expended on developing effective approaches to prevent infection by bacteria and other microorganisms in this setting. Many of these strategies have fallen out of favour, having foundered on grounds of expense, patient unacceptability and conse- quent problems with compliance, and a lack of convincing scientific evidence to support their efficacy. One practice that has proved more durable than most is the use of antibacterial prophylaxis (ABP). This approach is not without its detractors and, given the problems attributed to ABP that have emerged in recent years, a re-examination of its risks and benefits is warranted. When ABP was first introduced, Gram-negative bac- teria—particularly members of the Enterobacteriaceae and Pseudomonas aeruginosa—were the most important bacterial pathogens encountered in neutropenic patients; infections were associated with significant case-fatality rates. Many of these bacteraemias were deemed to be autocthonous in origin, with the gut being the most likely source. The concept of 'colonization resistance', which underpinned the rationale for ABP, was developed by van der Waaij and co-workers 2 (reviewed in reference 3) following observations in laboratory animals. Mice with their own normal gut flora were able to resist colonization when challenged by exogenous Gram-negative aerobic bacteria, unless these were administered in very high doses. Conversely, in gnotobiotic mice, colonization was achieved by inocula of 10-100 organisms. Germ-free mice that had first been colonized by anaerobic flora were able to resist colonization nearly as well as normal controls. Extra- polating this concept to humans, it was argued that preven- tion of infection from gut-derived Gram-negative bacteria during neutropenia could be achieved by administering antimicrobials that would selectively target these bacteria and that would leave the 'beneficial' anaerobes intact. Initial regimens comprised cocktails of orally administered non-absorbable antibacterials, often in conjunction with a polyene antifungal. Frequently, these agents were used in combination with oral antiseptics. These protocols were problematic to administer and patient compliance was poor. Experience with this approach to ABP was mixed and results derived from published studies are difficult to analyse because of differences in the combinations used, the frequency of administration of the agents involved, and in the degree and duration of neutropenia experienced by trial subjects. In addition, there were variations in the timing of commencement of ABP relative to the onset of neutropenia and also in adjunctive measures such as dietary manipulation or nursing of patients in laminar air flow environments.