Infections are common in cancer patients with neutropenia (an absolute neutrophil count [ANC] <500/mm³ or a count of <1000 cells/mm³ with a predicted decrease to <500 cells/mm³). Since these infections are associated with complications, and because fever is often the first and only sign of infection, current treatment guidelines recommend administration of parenteral empirical broad‐spectrum antibiotics as well as keeping patients hospitalized until the clinical signs of infection disappear (Bodey 1966; Hughes 1997; Hughes 2002).

Febrile neutropenic patients have heterogeneous outcomes; approximately 50% to 60% of patients do not develop life‐threatening complications or fatal infections (Mullen 1990; Buchanan 1993; Orudjev 2002), between 48% and 60% have established or occult infections, and around 20% or more of patients with profound neutropenia (neutrophil counts <100 cells/mm³) have bacteremia. A very small percentage, 4% to 6%, die as a consequence of a severe bacterial infection (Talcott 1988; Talcott 1992; Santolaya 2002). Thus, according to the different clinical features and outcomes, febrile neutropenic episodes might be regarded as low or high‐risk for complications. In low‐risk episodes, patients are stable and rarely develop complications; in contrast, patients with high‐risk episodes have substantial co‐morbidities such as, hypotension, respiratory failure, dehydration or uncontrolled bleeding (Talcott 1988; Santolaya 2002).

Recently, identification of low‐risk patients has been very useful for providing less aggressive empirical antimicrobial therapy resulting in risk predictive models being created to select low‐risk patients. These prognostic scales are based on laboratory and clinical findings during the initial patient assessment in the routine clinical setting (Talcott 1992; Elting 1997; Klaassen 2000; Mesters 2000; Soker 2001; Santolaya 2002).The first scale was developed and validated in 1988 by Talcott et al (Talcott 1988; Talcott 1992). In 2000, an international prospective study established an improved risk assessment model, based on clinical criteria –the Multinational Association for Supportive Care (MASC) index. (Klastersky 2000). Current guidelines for adult cancer patients recommend using this scale to classify febrile neutropenia episodes (Hughes 2002). For pediatric patients, different scales have been proposed (Alexander 2002; Santolaya 2002) but specific recommendations for their use have not been published (Hughes 2002).

Most patients with a febrile neutropenic episode at the emergency department show no apparent infection source, in approximately 30% the infection is localized, mainly in upper respiratory tract or skin, and in 20% to 40% of them the episode can be microbiologically documented. Regarding the microbial organisms that cause infections in febrile neutropenic patients, it has been observed that the incidence of Gram‐negative organisms has declined and Gram‐positive infections account for 60% to 70% of all microbiologically documented infections (Hughes 2002; Kamana 2005). Accordingly, recommendations for empirical antimicrobial therapy have changed during the last decades, but the general principle for the selection of antimicrobial agents still remains: broad‐spectrum antibiotics with activity against Gram‐negative and Gram‐positive bacteria. In particular for low risk patients, recommended regimens include different antibiotic schemes, including monotherapy, combinations, by oral or parenteral route. Some examples are amoxicillin with clavulanate (Klaassen 2000a; Gupta 2009), ciprofloxacin (Freifeld 1999; Hidalgo 1999), ceftriaxone (Sebban 2008; Gupta 2009), or aztreonam‐clindamycin (Rubenstein 1993).

A meta‐analysis comparing the effectiveness of empirical antibiotic therapy, either orally or intravenously was published in 2004. After the evaluation of 18 clinical trials, results demonstrated that oral treatment is as safe as the intravenous antibiotic treatment in febrile neutropenic patients, since death and failure rates were similar for both methods: Relative risk (RR) 0.95 (95% Confidence interval (CI) 0.54 to 1.68) and RR 0.95 (95% CI: 0.85 to 1.07), respectively (Vidal 2004).

Current recommended empiric antimicrobial treatment for low‐risk febrile neutropenic patients are based on multiple clinical trials and observational studies. In these studies the authors have assessed different types of antibiotics and less aggressive strategies, such as, sequential intravenous to oral therapy or early hospital discharge with continued outpatient therapy. A number of clinical trials have evaluated the effectiveness of in‐hospital administered oral antibiotics (Klaassen 2000a; Kamana 2005). In children, Paganni et al. used ciprofloxacin in low‐risk patients after intravenously broad‐spectrum antibiotics (Paganini 2001). In another study, 126 episodes were evaluated. In‐hospital intravenous ceftriaxone showed a success rate of 78%, which was similar (76%) when the same treatment was administered at‐home (Karthaus 1998). Meanwhile, Mustafa et al. demonstrated the safety of outpatient ceftriaxone treatment in a pilot study with 19 children; 18 patients completed at‐home treatment and only one required hospitalization as fever persisted for over 48 hours (Mustafa 1996). Another clinical trial showed an 89% success rate with ciprofloxacin as ambulatory treatment, after a 24 hour hospital stay. In this study, patients who needed re‐hospitalization completed treatment intravenously without complications (Malik 1995). Other forms to deliver empirical antimicrobial treatment to low‐risk patients include at‐home administration of short‐term antibiotic schemes (Cherif 2004; Chamilos 2005; Cherif 2006) or the suspension of antibiotics after the first 24 hours (Nijhuis 2005).

In general, the outcome measures used to evaluate the empirical antibiotic therapy in low‐risk patients include defervescence after initiating the antibiotics (Chamilos 2005), hospital readmission (Malik 1995), treatment failure (change of initial empirical antibiotic scheme) (Mustafa 1996), death (Malik 1995; Mustafa 1996), adverse events and costs (Santolaya 2004). Some authors (Freifeld 1999; Kern 1999; Kamana 2005) suggest that oral antibiotic therapy improves quality of life (QoL) but this outcome has not been assessed.

Interestingly, although there are some clinical trials that show the effectiveness and safety of outpatient antimicrobial therapy for low‐risk pediatric patients, in a study that explored the feasibility to deliver this type of therapy, 71% of health‐care professionals and 53% of parents would choose ambulatory therapy (Sung 2004). This could suggest that both patients and health‐care professionals have doubts about the safety of this type of treatment. Quezada et al. corroborated these findings in an observational study with children experiencing fever and neutropenia; in about one‐quarter of episodes either the family or treating physician did not find the prospect of outpatient care appealing (Quezada 2007). Maybe this issue is related to the side effects reported (Kamana 2005), because some patients treated as at‐home have needed new hospitalization (Elting 2008), or because this approach requires an organized approach and 24 hours, 7 days per week response capacity, educational strategies for families and health‐care professionals, as well as a good doctor‐patient relationship (Hughes 2002;Santolaya 2010).

In 2008 Carstensen and Sorensen published a systematic review about the effectiveness and safety of outpatient febrile neutropenia management of low‐risk cancer patients. They included only clinical trials in adult patients and even though they concluded that outpatient empirical antimicrobial therapy is safe, effective and comparable to hospital‐based therapy, three of the nine studies selected were trials without a control group (Carstensen 2008).

Considering that outpatient management in recent years has become an alternative for febrile neutropenia low‐risk patients and the amount of publish studies with this approach has increased, this systematic review aims to analyze the efficacy and safety of ambulatory antimicrobial therapy in cancer patients with febrile neutropenia.