Miguel A Sanz Alonso Departments of Haematology and Infectious Diseases, University Hospital La Fe , Isidro Jarque Ramos , Miguel Salavert Lletí Departments of Haematology and Infectious Diseases, University Hospital La Fe

Originally printed in:
» European Oncological Disease 2006 - September 2006

Infectious complications are the most common cause of morbidity and mortality in cancer patients, particularly in those with chemotherapy-induced neutropenia. Over the past several decades substantial progress has been made in the management of febrile neutropenia (FN). Empirical antibiotic therapy has reduced mortality rates dramatically in the setting of FN and prompt initiation of antimicrobial therapy with broadspectrum antibiotics at the onset of fever remains the gold standard. Combination therapy with a beta-lactam plus an aminoglycoside has proven to be effective, although related toxicity is of concern. Consequently, there is an increasing use of monotherapy with carbapenems, antipseudomonal penicillins and third- or fourthgeneration cephalosporins instead of classic combination therapy.

A marked shift in the spectrum of causative organisms towards a gram-positive predominance has been the main factor influencing therapeutic approaches. Epidemiology of infection is influenced not only by the severity and duration of neutropenia, but also by the intensity of chemotherapy, the use of prophylaxis and/or empirical antibiotic therapy, the use of central venous catheters, environmental factors and duration of the hospital stay, among others.

The detection of epidemiological shifts requires frequent monitoring and surveillance, particularly at centres treating large numbers of patients, as institutional differences can be substantial. For example, in recent years, some hospitals have experienced an increase of infections caused by multidrug-resistant gram-negative bacilli, such as Acinetobacter species or Stenotrophomonas maltophilia, and gram-positive cocci with increasing resistance to glycopeptides.

Many reports have demonstrated the emergence of gram-positive organisms in patients with neutropenia. They may account for 45–70% of microbiologically documented infections with bacteremia in patients with neutropenia, although the majority of them are coagulase-negative staphylococci, which have limited virulence. Focusing only on bloodstream infections may result in an misleading picture, as only 15–25% of patients with neutropenia develop a bloodstream infection and bloodstream infections are caused predominantly by gram-positive cocci, whereas infections at most other sites are predominantly gram-negative or polymicrobial. In contrast many gram-negative pathogens are extremely virulent, so empirical therapy must always include coverage for Pseudomonas aeruginosa and any other gramnegative organisms that are common within a given institution. Clinicians should therefore consider the entire spectrum of bacterial infection, not only bloodstream infections, when initiating empirical anti-biotic therapy.

Although overwhelming streptococcal sepsis has raised particular concern, the indiscriminate empirical use of glycopeptides should be discouraged. Treatment with glycopeptides can and should be stopped for those patients whose blood cultures show no growth at 72 to 96 hours. Early empirical antifungal therapy with amphotericin B has been considered a standard practice in cases of persistent fever in high-risk patients despite broadspectrum antibacterial coverage. Alternatives to amphotericin B (AMB) now exist, including lipid formulations of this drug, and recently licensed antifungal drugs, such as caspofungin and voriconazole, are new options for empirical antifungal therapy that are used increasingly because of their safer toxicity profile. It is critically important that each patient be carefully re-assessed before starting antifungal therapy, because there are many other potential causes for persistent fever, including resistant bacteria and viruses.

There is a growing interest in designing riskadapted strategies for the management of FN. The administration of parenteral, broad-spectrum empirical antibiotic therapy after the hospitalisation of patients with FN is the accepted standard of care. This approach is effective (with an infectionrelated mortality rate of less than 10%) but is expensive and, when applied to all patients with FN, may represent a suboptimal use of resources. Over the past decade, the development of risk stratification models has allowed for the identification of low-risk patients with additional treatment strategies, such as initial hospitalisation followed by early discharge with parenteral or oral antibiotics (sequential therapy) and out-patient treatment with oral antimicrobials. The most attractive option is out-patient treatment for the entire febrile episode, because of several advantages, including important repercussions on economic costs and quality of life, as well as a significant reduction in nosocomial superinfections. Careful selection of patients at a low risk of developing complications, appropriate empirical regimens and the daily monitoring of patients (for response and toxicity) are critical for the success of this approach. Expected duration of neutropenia (less than 10 days and under 60 years of age) and favourable social and economic environment, with access to prompt medical attention, are relevant prerequisites for considering this approach.